Como afrontar células madre de cáncer con alimentos

Como Afrontar Células Madre de
Cáncer con Alimentos y Plantas
Alejandro Sacha Barrio Healey

Primera Teoría
Darwinismo interno

Cáncer como una mutación monoclonal
• La teoria de los años 90 sobre el cancer fue que
era una mutacion genetica única, causada por
radiacion, tabaco u otro agente mutagenico, que
inducia hacia la malignidad de la celula.
• Esta celula se divide exponencialmente dando
lugar a una “poblacion clonal” de celulas
malignas identicas que conforman el tumor.
• La quimioterpia o cirugia serian la unica opción.

Heterogeneidad de un Tumor
• Biopsia de 9 regiones del cuerpo de un paciente.
• 33% Monoclonal (la misma mutación genética)
• 45% Compartían algunas mutaciones pero otras no
• 20% Mutaciones únicas en de la biopsia en la zona
• Se concluye que la mayoría de mutaciones de un tumor, muestra
diferencias significativas dependiendo de la zona del cuerpo.
• Esta información señala la hetereogenicidad intra
tumoral, y que la configuración de un tumor es no
uniforme desde el punto de vista genético, hay un
grado singularidad en cada tumor en cada región del
cuerpo.
•
• MATTHEW R.G. TAYLOR, M.D., PH.D

Darwinismo interno
Darwinismo Oncológico
• Dr. Marco Gerlinger del Cancer Research UK
London Research Institute señala que el
cancer puede ser conceptualizado como una
coleccion de celulas heterogeneas que
continuamente evolucionan y hasta compiten
de forma Darwiniana, por su derecho a existir
a expensas del hospedero.

Selección natural interna
• Se sugiere que varias fuerzas de la seleccion
natural, incluyendo la exposición a la
quimioterapia, propelen la selección
Darwiniana, mientras que los tumores se
adaptan en formas que favorecen el
crecimiento y la propagacion.

Problemas con el Darwinismo interno
• The appeal to “internal” Darwinism to account for the multiplicity
of cancer traits as merely “lucky accidents” of evolution (unlucky for
the patient of course), falls short of a full explanation, however.
• Es un rasgo fundamental de la evolucion que las mutaciones al azar,
son casi siempre perjudiciales. Sin embargo, las mutaciones que
conducen al cancer son “afortunadas” en una sospechosa y
frecuente numero de ocasiones.
• ¿Por qué la mayoria de mutaciones de celulas tumorales no
conducen a una mal adaptacion y eventualmente muerte de la
celula?, tal como sucede con las celulas sanas?
• Aparentemente en vez de fatalmente alterar la maquinaria de las
celulas, estas drasticas mutaciones tiene el efecto opuesto, en
efecto otorgan una acrecentada sobrevivencia de la célula.

• La pregunta que surge es si el cáncer son
mutaciones casuales y fortuitas, como
siempre hemos supuesto, ¿ o mas bien habría
un grado de inteligencia en el Cáncer?

Problemas con la hipótesis de la
celula rebelde
• 1. NO explica el alto grado de organizacion y
cooperación entre las células de cancer.
• 2. El segundo problema es que no explica la
habilidad del cancer a desplegar una increible
variedad de trucos de sobrevivencia.

¿El cáncer es un caos celular?
• 1. Los tumores son capaces de generar su propia irrigación
sanguínea (angiogénesis)
• 2. Secretar enzimas que las protegen contra el sistema
inmunológico que y les permite viajar por el cuerpo.
• 3. Desactivar genes supresores del cáncer
• 4. Pueden alterar su metabolismo para sobrevivir en
medios de hipoxia y acidez, se adaptan al medio en que se
encuentra para asegurar su supervivencia
• 5. Posee una singular capacidad de migrar hacia otros
tejidos.
• 6. Prospera en la hipoxia.
• 7. Se adapta a fuentes de combustible.

Rasgos del Cáncer
• 1. Silencia genes supresores de cancer
• 2. Desactiva la genética la apoptosis
• 3. Anoikis (muerte programada de celula una vez liberada de la matriz extracelular.)
• 4. Desactiva la señilidad celular fabricando enzimas que reparan la erosion de telomeros.
(Hanahan & Weinberg 2000
• 5. Evaden el sistema inmunologico retirando receptores de la membrana
• 6. Transforman las propiedades viscoleasticas de la celula para facilitar motilidad, invacion y
colonizacion. (Butcher, Alliston & Weaver, 2009)
• 7. Secretan enzimas corrosivas que disuelven membranas duras, permitiendo a la celula
ingresar a la sangre y sistema linfatico circulatorio., para distribuirse por el cuerpo.
• 8. Prosperan en medios de hipoxia y desactivan lel metabolismo de oxidacion – fosforilacion
de las celulas sanas. Usando el ciclo glucolitico , efecto warburg. Warburg 1956)
• 9. Toleran el resultante pH bajo mejor que celulas sanas, escudandose de las alarmas
contra” células foraneas” dentro de los organos que invaden.
• 10 . Manufacturan sus propias señales mitogenicas y factores de crecimiento haciendolas
independientes señales de replicacion. (Hanahan & Weinberg 2000)
• 11. Alteran las prpiedades quimicas y fisicas de la matriz extracelular para optimizar crecimiento tumoral y
sobrevivencia.

¿Caos celular o inteligencia oculta?
• Because of their pre-existing nature, cancer adaptations should more accurately be
called exaptations (Gould & Vrba 1982). Here an analogy might be helpful.
Cancer’s acquisition of ancient traits could be compared to the memory card game
in which all the cards are laid out in prearranged order face down, and then turned
over one by one at random. Initially the distribution of face-up cards looks chaotic,
but once a large subset of the cards is turned over the order becomes apparent.
The emergence of pre-existing order by random uncovering is clearly vastly more
efficient than the generation of the same order ab initio by a Darwinian process of
blind trial and error. Of course, the pre-existing order represented by cancer genes
(the toolkit) was the product of a Darwinian process, but one that took place, not
in the host organism over a few years, but in its ancestors hundreds of millions of
years ago. Thus we distinguish between acquiring genes from parents (Darwinian
evolution, vertical gene transfer), acquiring genes from peers (Lamarckian
evolution, horizontal gene transfer) and reactivating the genes of distant ancestors
(the atavism known as cancer). We do not claim that internal Darwinism is
irrelevant to the progression of neoplasms. Rather that atavistic transformations
are a relatively rare part of normal Darwinian evolution but that they play the
dominant role in the progression of cancer.

Teoria 2
Metazoan 1.0" --The 1.6 Mil millones
de años de Evolucion del Cancer
• La hipótesis central es que el cáncer un proceso de programas pre-
organizados impulsado por un “ software genético, genes
ancestrales profundamente evolucionados, y de un sistema de
genes que son activos un estadio temprano del desarrollo del feto,
y el cual se vuelve inapropiadamente re activado en el adulto.
• En efecto tumores cancerosos son atavismos, que provienen de
formas de vida antigua, provienen de las primeras formas de
organismo multicelulares. ( Metazoa 1.0)
• Cancer tumors as Metazoa 1.0: tapping genes of ancient ancestors
• P.C.W. Daviesa and C. H. Lineweaverb

• El cáncer no es un grupusculo de celulas rebeldes y anarquicas, pero mas bien eficaz sistema pre-
programado como respuesta al estress, reactivado desde un remoto período de evolution.
• Metazoa 1.0 Normalmente esta guardado bajo llave, suprimido por la maquinaria de genes
posteriores usados para los planes mas sofisticados del cuerpo. Si algo abre esta cerradura
genetica, los genes ancestrales se expresan, y aparecen una forma de vida muy resitsente, un
adversario formidable.
• Vemos al cancer como la ejecucion de un programa antiguo re-activado en el genoma de las
celulas. Es un relapso hacia un fenotipo ancestral.
• Esta nueva teoria predice que mientras el cancer progresa, estadios cada vez mas malignos
progresan, se expresaran genes mas profundamente conservados en organismos multicelulares.
• Debido a que realizan funciones absolutamente críticas en estados tempranos del desarrollo
embrionario.
• Los genes activos en el embrion, y que son normalmente latentes y durmientes en la vida adulta,
son reactivados en el cancer. Estos mismo genes embrionarios son tambien los genes antiguos, que
se ubican profundamente arraigados en arbol de vida multicelular.
• Recent genetic studies of a freshwater Hydra indicate that the human oncogene myc dates back at least 600 million

• LA hipotesis central es que el cancer es una
estado de atavismo de vida multicelular.
• Los atavismos ocurren debido a genes
ancestrales que son preservados en el genoma
aunque desactivados, o relagados como
segmentos no codificantes del ADN.
• Here we propose that cancer is an atavism
associated with ancestral cellular functions
regulated by genes that have been largely
suppressed for more than 600 million years.

• If tumors are a type of living fossil from the
era of Metazoa 1.0, we might expect to find
genetic and even fossil evidence.

• Recent genetic studies of a freshwater Hydra indicate that
the human oncogene myc dates back at least 600 million
years (Hartl et. al., 2010) and more comprehensive studies
are revealing even older dates (Srivastava et al
2010).Weinberg (1983) speculated on the implications of
the fact that the genes that cause cancer are ancient and
highly conserved: “Such conservation indicates that these
genes have served vital, indispensable functions in normal
cellular and organismic physiology, and that their role in
carcinogenesis represents only an unusual and aberrant
diversion from their usual functions.” It has become clear
that the genes responsible for the cellular cooperation
necessary for multicellularity are also the genes that
malfunction in cancer cells (Weinberg 2007)

Metazoa 1
• These proto-metazoans were
effectively small, loosely-knit
ecosystems that fell short of
the complex organization and
regulation we associate with
most modern metazoans. In
short, proto-metazoans,
which we dub Metazoans
1.0, were tumor-like
neoplasms
Metazoa 2
• By 600 million years ago,
Metazoa 2.0 had emerged.
• These organisms have a richer
repertoire of biological
processes needed to coordinate
a larger number of highly
differentiated cell types. They
are characterized by
sophisticated genetic and
epigenetic command and
control systems familiar from
modern complex organisms
such as humans.
The genetic apparatus of the new Metazoa 2.0 was overlain on the old genetic
apparatus of Metazoa 1.0.
and when things goes wrong (often in senescence of the organism) with the nuanced
overlay that characterizes Metazoa 2.0, the system may revert to the ancient, more
robust way of building multicellular assemblages Metazoa 1.0. The result is cancer.
In evading one layer of genetic regulation – turning proto-oncogenes into oncogenes –
cancer mutations uncover a deeper, older layer of genes that code for behaviors that
are often able to outsmart our best efforts to fight them.

• Organisms may suffer mechanical damage such
as wounding or inflammation (hardware insult),
or genetic damage such as DNA base pair mis-
copying (software insult), and as a result, they flip
to Safe Mode, unlocking the ancient toolkit of
Metazoa 1.0. Just as a computer deals with this
crisis by performing system checks and
corrections, so too will modern organisms run
through a collection of reviews and strategies to
repair the damage. If DNA cannot be repaired,
there are secondary DNA repair mechanisms.

• The genetic or epigenetic mutations that open up access to
pre-existing adaptations can be caused by chronic
inflammation, viral infections or other environmental
causes.
• If these fail and the cell begins to proliferate, cell signaling
and growth inhibitors try their luck. If these fail to stop
proliferation, there is another line of defense – apoptosis
(programmed cell death). There is also the immune system.
If all these fail, the outcome is malignant uncontrolled
growth. It is because cancer is the Metazoan 1.0 default
option that it is relatively easy to start and hard to stop.
Cancer can be triggered in a wide variety of ways, but once
it becomes established it is extremely hard to reverse

Si la teoría es correcta, investigadores encontraran que
estados malignos del cáncer, re-expresan genes de los
estadios mas tempranos de embriogénesis.
• El prominente embriólogo escocés,
doctor John Beard (1858 – 1924)
tuvo la lucidez de observar que
células embrionarias se comportan
de manera similar a las células de
cáncer.
• 1. Comparten el hecho que se
reproducen con acelerado ritmo
• 2. Tienen gran capacidad de
producir vasos sanguíneos.
• 3. Poseen sofisticados mecanismos
de resistencia al sistema
inmunológico.

Las células de cáncer tienen cinco
cualidades básicas:
• Pierden diferenciación, mientras más agresivo es el tumor,
menos se parece a su tejido original.
• Proliferan sin restricción.
• Son invasivas, tienen la capacidad de invadir el epitelio.
• Son angiogénicas, tienen la habilidad de producir nuevos
vasos sanguíneos.
• Migran, generan metástasis.
• Por otro lado, tenemos los trofoblastos (trofo quiere decir
alimentar y blasto, germinador), que son células que se
forman desde la capa más externa del blastocito del
embrión, y su función es darle nutrientes, son las primeras
células en diferenciarse del óvulo fertilizado, y son muy
cercanas al estado de célula madre.

Cancer Stem cell
Célula Madre de Cancer

La Hipótesis
• Desde el punto de vista clínico la hipótesis de las CM del
cáncer plantea una explicación de por qué pacientes con
cáncer tienen una recaída después de radio o quimio terapia.
Si la CM de cáncer es resistente al la terapia, son estas células
las que hace que rebrote la enfermedad después de la
retirada de las Quimioterapia.
• Debe notarse que el nombre CM de cáncer, no
necesariamente se origina de CM normales. Las CM de cáncer
pueden originarse de mutaciones en los progenitores de CM
sanas, sin embargo, también es posible que se originen de
células maduras y diferenciadas. Los orígenes de la formación
de CMC son objeto de intenso estudio.

Interleukin 6
• Key driver of CSC
• Inflamatory citoquines
• Stress and inflamation activate IL6
• Meditation lower IL6
• Diet and excersise lowers IL6

Interleukin 8
• Dying cells make Interleukins in organ, and
stimulate stem cells to repair.
• Immune regulators, IL8 a inmune regulator.

Tumor angiogenesis
• Antiangiogenesis therapies
• Avastatin 2004 Bevacizumab
• Nexavar 2005 Sorafenib
• Stutent 2006 Sunitinib malate
• Though the time to grow the tumor, was delayed, then the
tumor came back more agressive. FDA removed license.
The antiangiogenic therapy was inadveratnlty stimulating
CSC.
• With antiangiogenesis drugs the CSC rises. Its physiological
response, if choke the blood supply, you are depriving the
tumor cells of oxygen, hypoxic, cancer cells love hipoxia.
Stem cells go up.

Metastasis
• Only cancer stem cells are metastatic
• They stay in dormant stage
• Stems cells are highly resistant to Chemotherapy
• Regular Cancer cells dont metastasize
• Shrinking tumors does not extend life. As the
tumor shrinks, the percentage of CSC rises.
• CSC are not evenly distributed in the tumor. So
how can we asses? How to isolate CSC
circulating?

Terapia convencional del cáncer vs terapia
especifica a célula madre de cáncer

• A pesar que la Quimioterapia puede reducir a
masa del Tumor, una poblacion agresiva de CMC
puede resistir los farmacos de la Quimioterapia,
dando lugar a recaida y multiresitencia a
farmacos. Por ejemplo:
• CMC de glioblastomas fue mas resitente a
agentes de quimioterpia como
temozolamide,carboplatino,paclitaxel, etoposide,
a comparacion que las celulas tumorales no CMC

Las Células Madre de cáncer tienen 3
propiedades:
• 1. Auto-renovación
• 2. Multi-potencia
• 3. Alta capacidad proliferativa

1. Autorenovación
• Es la capacidad de las celulas a realizar
division simetrica o asimetrica.
• SIMETRICA: LA celulas produce dos celulas
hijas diferenciadas.
• ASIMETRICA: Da lugar a una celula
diferenciada y otra célula madre.

Experimento
Células primarias de cáncer de colon.
• CD133 con las CM de cáncer formó tumor en ratón.
• CD133° sin CM de cáncer, pero con células que conforma la
masa principal del tumor,  no formó tumor en ratón.
• Esta se aisló, y transplantó en ratones, transplante secundario
y terciario de CD133° continuo creando tumores,
demostrando la capacidad de autorenovacion de las CMC
• Obrien et al.

2.Multipotencia
• Es la habilidad de las CMC a diferenciarse
dentro de la población de celulas
heterogéneas del tumor.

3. Alta capacidad proliferativa
• Para formar una colonia de tumor se
necesitan millones de celulas del tumor
primario.
• Para formar un tumor nuevo a partir de CMC
solo se requieren 100 células.

• Células Madre normales tienen 2 habilidades:
• 1. Repoblación del órgano del que constituyen.
• 2. Propagarse a ellas mismas.
• Las CM del cáncer cumplen estas mismas funciones
pero no están con las mismas limitaciones genéticas
que las CM normales. Por ejemplo, presentan
mutaciones en Hedgehog, WNT y Notch.
Adicionalmente se sabe que CMC son importantes en
la regulación del Cáncer.

GENES de Célula Madre CM
• Mecanismos de auto-renovación de CM
• Genes involucrados en mantenimiento y
renovación de CM
• 1. Hedgehog
• 2. WNT
• 3. NOTCH

HEDGEHOGHh
• Hh, simetria Izq Der del sistema nervioso,
esperamatogenesis, organogenesis.
• Perturbaciones en la fiosiologia de Hh estan
asociados CM de cancer en glioblastomas,
mieloma multiple y cancer de mama.
• El primer fitoquimico que ha mostrado inhibir
al camino Hh es ciclopamina, un compuesto
encontrado tne Veratrum californicum, corn
lily.

WNT
• WNT/ß catenin
• Involucrado en varios procesos, incluyendo el mantenimiento
de la CM en tejidos adultos. WNT es una proteína extracelular
que activa la Lipo-proteina de Baja Densidad. Mutaciones en
WNT están involucrados en varios tipos de cáncer, e
implicados en la capacidad de la CM de cáncer a auto
renovarse. Varias sustancias han mostrado la capacidad de
inhibir a WNT en CM de cáncer, tales como:
• Vitamina D
• Selenio
• EGCG

• Curcumin inhibits Wnt/beta-catenin signaling The Wnt/beta-catenin signaling
pathway is tightly regulated and has important functions in development, tissue
homeostasis, and regeneration.
• Its deregulation is frequently found in various human cancers. Activation of
Wnt/beta-catenin signaling has been found to be important for both initiation
• and progression of different cancers. Several reports suggest that curcumin and its
analog (CHC007) are good inhibitors of b-catenin/Tcf signaling in gastric, colon, and
intestinal cancer cell

Notch
• Las señales de Notch se activan por contacto directo entre celulas. En
celulas sanas Notch esta involucrado en una variedad de procesos de
desarrollo, como desarrollo del Sistema Nervioso Central, desarrollo del
sistema vascular, organogenesis, y generacion de CM en Hematopoesis.
Señales aberrantes de Notch estan involucradas en renovar el crecimiento
tumoral en medulo blastomas, se ha visto que Notch se encuentra
enriquecido en celulas tumorales del cerebro. Inhibicion de Notch ha
resultado en apoptosis de CM de cáncer, y bloquea fromacion de tumor
xenograft.
• El fitoquimico Resveratrol encontrado en uvas y Poligonum cuspidatum.
Este fitoquimico afecta Notch post translational, ya que niveles de Notch
en mRNA no fueron afectados.
• Leucemia linfoblastica aguda…..Resveratrol reduce expresion de proteinas
Notch.

• Fig. 2. Plant derived compounds affecting cancer (stem) cell metabolism. CSCs, like normal (non-tumor) stem cells, are characterized by a higher glycolytic
metabolism
• (aerobic glycolysis or Warburg effect) and a lowered mitochondrial respiration, compared to more differentiated and/or committed cells within the tumor mass.
Several phytochemicals are known to inhibit glucose transportation (es. GLUTs) and glycolysis related enzymes, inducing the expression/activation of TCA cycle and
OXPHOS related enzymes. Abbreviations: HIF-1, hypoxia inducible factor-1; GLUTs, glucose transporters; HK-II, hexokinase-II; LDH-A, lactate dehydrogenase A; PPP,
pentose phosphate pathway; mTOR, mammalian target of rapamycin; Akt, or protein kinase B (PKB); ERK, extracellular signal-regulated kinase; TCA, tricarboxylic acid
cycle; AMPK, AMP-activated protein kinase.

Extracto de Te verde EGCG
Epigalo Catequina Gallato
• Epigallocathechin gallate, polyphenol present in green tea, inhibits stem-like characteristics and epithelial-mesenchymal transition in
nasopharyngeal cancer cell lines.
• Lin CH1, Shen YA, Hung PH, Yu YB, Chen YJ.
• Author information
• Abstract
• BACKGROUND:
• Previous studies have demonstrated that the consumption of green tea inhibits the growth of various cancers. Most cancers are believed to be
initiated from and maintained by a small population of cancer stem-like cells (CSC) or tumor-initiating cells (TIC) that are responsible for tumor
relapse and chemotherapeutic resistance. Although epigallocathechin gallate (EGCG), the most abundant catechin in green tea, has been reported to
induce growth inhibition and apoptosis in some cancer cells, its effect on CSC is undefined. In this study, we enriched CSC by the sphere formation,
and provided an efficient model for further experiments. Using this method, we examined the effects of EGCG regulating the nasopharyngeal
carcinoma (NPC) CSC and attempted to elucidate the possible mechanisms.
• METHODS:
• NPC TW01 and TW06 cell lines were enriched by sphere formation and characterized their phenotypical properties, such as invasion capacity,
epithelial-mesenchymal transition (EMT) and gene expression were analyzed by quantitative real-time reverse transcription polymerase chain
reaction (q-RT-PCR). EGCG-induced growth inhibition in the parental and sphere-derived cells was determined by MTT and bromodeoxyuridine
(BrdU) assay. EGCG-induced apoptosis was analyzed by flow cytometry with Annexin V and PI staining. The effects of EGCG on sphere-derived cell
tumorigenicity, migration and invasion were determined by soft agar assay, wound healing, and cell invasion assay. The alternation of protein
expression regulated by EGCG on these sphere-derived cells was assessed by immunofluorescence staining and western blot.
• RESULTS:
• NPC sphere-derived cells grown in serum-free non-adherent culture showed increased expression of stem cell markers and EMT markers compared
to parental cells grown in conventional culture. Although EGCG induced growth inhibition and apoptosis in the parental cells in a dose-dependent
manner, it was not as effective against spheres. However, EGCG potently inhibited sphere formation and can eliminate the stem cell characteristics
of NPC and inhibit the epithelial-mesenchymal transition (EMT) signatures.
• CONCLUSIONS:
• Overall, these findings show that NPC cells with sphere formations possess the properties of CSC. Using this model, we found that EGCG regulated
NPC CSC, their self-renewal capacity, and inhibited their invasive characteristics. It supports the pivotal role of EGCG as a dietary compound targeting
NPC and may decrease recurrence and metastasis in nasopharyngeal carcinoma cell

Curcumin and epigallocatechin gallate inhibit
the cancer stem cell phenotype via down-regulation
of STAT3-NFκB signaling.
• Chung SS1, Vadgama JV2.
• Abstract
• BACKGROUND/AIM:
• The cancer stem cell (CSC) model postulates the existence of a small proportion of cancer cells capable of
sustaining tumor formation, self-renewal and differentiation. Signal Transducer and Activator of Transcription 3
(STAT3) signaling is known to be selectively activated in breast CSC populations. However, it is yet to be
determined which molecular mechanisms regulate STAT3 signaling in CSCs and what chemopreventive agents are
effective for suppressing CSC growth. The aim of this study was to examine the potential efficacy of curcumin and
epigallocatechin gallate (EGCG) against CSC and to uncover the molecular mechanisms of their anticancer effects.
• MATERIALS AND METHODS:
• To suppress the CSC phenotype, two breast cancer cell lines (MDA-MB-231 cells and MCF7 cells transfected with
HER2) were treated with curcumin (10 μM) with or without EGCG (10 μM) for 48 h. We used tumor-sphere
formation and wound-healing assays to determine CSC phenotype. To quantify CSC populations, Fluorescence-
activated cell sorting profiling was monitored. STAT3 phosphorylation and interaction with Nuclear Factor-kB
(NFkB) were analyzed by performing western blot and immunoprecipitation assays.
• RESULTS:
• Combined curcumin and EGCG treatment reduced the cancer stem-like Cluster of differentiation 44 (CD44)-
positive cell population. Western blot and immunoprecipitation analyses revealed that curcumin and EGCG
specifically inhibited STAT3 phosphorylation and STAT3-NFkB interaction was retained.
• CONCLUSION:
• This study suggests that curcumin and EGCG function as antitumor agents for suppressing breast CSCs. STAT3 and
NFκB signaling pathways could serve as targets for reducing CSCs leading to novel targeted-therapy for treating
breast cancer.

Curcumin
Curcuma-Palillo
• Curcumin and Cancer Stem Cells: Curcumin Has Asymmetrical Effects on
Cancer and Normal Stem Cells.
• Sordillo PP1, Helson L2.
• Abstract
• Curcumin has been shown to have numerous cytotoxic effects on cancer stem
cells (CSCs). This is due to its suppression of the release of cytokines, particularly
interleukin (IL)-6, IL-8 and IL-1, which stimulate CSCs, and also to its effects at
multiple sites along CSC pathways, such as Wnt, Notch, Hedgehog and FAK. In spite
of its multiple actions targeting CSCs, curcumin has little toxicity against
normal stem cells(NSCs). This may be due to curcumin's different effects on CSCs
and NSCs.
• Copyright© 2015 International Institute of Anticancer Research (Dr. John G.
Delinassios), All rights reserved.
• KEYWORDS:
• CXCR1; CXCR2; Curcumin; FAK pathway; Hedgehog pathway; Notch pathway; Wnt
pathway;cancer stem cells; interleukin-1; interleukin-6; interleukin-8; review

Curcumin: a promising agent
targeting cancer stem cells.
• Zang S, Liu T, Shi J, Qiao L1.
• Abstract
• Cancer stem cells are a subset of cells that are responsible
for cancer initiation and relapse. They are generally resistant to the
current anticancer agents. Successful anticancer therapy must consist of
approaches that can target not only the differentiated cancer cells, but
also cancer stem cells. Emerging evidence suggested that the dietary
agent curcumin exerted its anti-cancer activities via targeting cancer stem
cells of various origins such as those of colorectal cancer,
pancreatic cancer, breast cancer, braincancer, and head and neck cancer.
In order to enhance the therapeutic potential of curcumin, this agent has
been modified or used in combination with other agents in the
experimental therapy for many cancers. In this mini-review, we discussed
the effect of curcumin and its derivatives in eliminating cancer stem
cells and the possible underlying mechanisms.

Targeting breast stem cells with the cancer
preventive compounds curcumin and piperine
• Madhuri Kakarala,
• Abstract
• The cancer stem cell hypothesis asserts that malignancies arise in tissue stem and/or progenitor
cells through the dysregulation or acquisition of self-renewal. In order to determine whether the
dietary polyphenols, curcumin, and piperine are able to modulate the self-renewal of normal and
malignant breast stem cells, we examined the effects of these compounds on mammosphere
formation, expression of the breast stem cell marker aldehyde dehydrogenase (ALDH), and Wnt
signaling. Mammosphere formation assays were performed after curcumin, piperine, and control
treatment in unsorted normal breast epithelial cells and normal stem and early progenitor cells,
selected by ALDH positivity. Wnt signaling was examined using a Topflash assay. Both curcumin and
piperine inhibited mammosphere formation, serial passaging, and percent of ALDH+ cells by 50% at
5 μM and completely at 10 μM concentration in normal and malignant breast cells. There was no
effect on cellular differentiation. Wnt signaling was inhibited by both curcumin and piperine by 50%
at 5 μM and completely at 10 μM. Curcumin and piperine separately, and in combination, inhibit
breast stem cell self-renewal but do not cause toxicity to differentiated cells. These compounds
could be potential cancer preventive agents. Mammosphere formation assays may be a
quantifiable biomarker to assess cancer preventive agent efficacy and Wnt signaling assessment
can be a mechanistic biomarker for use in human clinical trials.

Curcumin inhibits breast cancer stem cell migration by
amplifying the E-cadherin/beta-catenin negative
feedback loop.
• Mukherjee S, Mazumdar M, Chakraborty S, Manna A, Saha S, Khan P, Bhattacharjee P, Guha D, Adhikary
A,Mukhjerjee S, Das T.
• Abstract
• INTRODUCTION:
• The existence of cancer stem cells (CSCs) has been associated with tumor initiation, therapy-resistance, tumor
relapse, angiogenesis and metastasis. Curcumin, a plant ployphenol, has several anti-tumor effects and has been
shown to target CSCs. Here, we aimed at evaluating (i) the mechanisms underlying the aggravated migration
potential of breast CSCs (bCSCs), and (ii) the effects ofcurcumin in modulating the same.
• METHODS:
• The migratory behaviour of MCF-7 bCSCs was assessed using cell adhesion, spreading, transwell-migration and 3D-
invasion assays. Stem cell characteristics were studied using flow cytometry. The effects of curcumin on bCSCs
were deciphered by cell viability assay, western blotting, confocal microscopy and si-RNA mediated gene-silencing.
Evaluations of breast cancer patient samples were performed using immunohistochemistry and flow cytometry.
• RESULTS:
• Here we report that bCSCs are endowed with aggravated migration property due to the inherent suppression of
the tumor suppressor, E-cadherin, which is restored by curcumin. A search for the underlying mechanism revealed
that in bCSCs, higher nuclear translocation of beta-catenin (i) decreases E-cadherin/beta-catenin complex
formation and membrane retention of beta-catenin, (ii) up-regulates the expression of its EMT-promoting target
genes including Slug, thereby (iii) down-regulating E-cadherin transcription to subsequently promote EMT and
migration of these bCSCs. In contrast, curcumin inhibits beta-catenin nuclear translocation thus impeding trans-
activation of Slug. As a consequence, E-cadherin expression is restored thereby increasing E-cadherin/beta-catenin
complex formation and cytosolic retention of more beta-catenin to finally suppress EMT and migration of bCSCs.
• CONCLUSIONS:
• Cumulatively, our findings disclose that curcumin inhibits bCSC migration by amplifying E-cadherin/beta-catenin
negative feedback loop.

Curcumin suppresses crosstalk between colon cancer stem
cells and stromal fibroblasts in the tumor microenvironment:
potential role of EMT.
• Buhrmann C1, Kraehe P1, Lueders C2, Shayan P3, Goel A4, Shakibaei M1.
• Abstract
• OBJECTIVE:
• Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk
between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially
on cancerstem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment.
• METHODS:
• Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro
with/without curcumin and/or 5-FU.
• RESULTS:
• Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancercells and fibroblasts and enhanced up-regulation of
metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation
associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-
cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC
survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116
compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but
dramatically decreased in the presence ofcurcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing
CSCs to 5-FU treatment.
• CONCLUSION:
• Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor
microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-
β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis.

Ellagic acid
Semilla y cascara de Granada
• Pomegranate extract inhibits the proliferation and viability of MMTV-Wnt-1 mouse
mammary cancer stem cells in vitro.
• Dai Z1, Nair V, Khan M, Ciolino HP.
• Abstract
• Pomegranate (Punica granatum L.) is known to possess anticancer activities. The effects of a
standardized extract of pomegranate (PE) on a mouse mammary cancer cell line (designated WA4)
derived from mouse MMTV-Wnt-1 mammary tumors were examined in this study. The WA4 cell
line has been previously characterized as containing a majority of cells possessing stem cell
characteristics. PE inhibited the proliferation of WA4 cells in a time- and concentration-dependent
manner. This was due to an arrest of cell cycle progression in the G0/G1 phase. PE was also
cytotoxic to quiescent WA4 cells in a concentration-dependent manner at concentrations >10
microg/ml. PE treatment of WA4 cells resulted in an increase in caspase-3 enzyme activity in a
time- and concentration-dependent manner, indicating that the cytotoxic effect of PE was due to
the induction of apoptosis. We tested the effect of several individual phytochemicals derived from
PE on WA4 cells. Ellagic acid, ursolic acid and luteolin caused a time- and concentration-dependent
reduction of cell proliferation and viability, suggesting that they contribute to the inhibitory effect
of PE, while caffeic acid had no effect. Cancer stem cells, which are highly resistant to conventional
chemotherapeutic agents, are thought to be the origin of both primary and secondary breast
tumors, and thus are a critical target in both breast cancer therapy and prevention. These data
suggest that PE, which is a proven and safe dietary supplement, has promise as an treatment
against breastcancer by preventing proliferation of cancer stem cells.

Pomegranate extract inhibits the proliferation and
viability of MMTV-Wnt-1 mouse mammary cancer
stem cells in vitro.
• Abstract

Sulforaphane
Brocoli
• Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells.
• Labsch S1, Liu L1, Bauer N1, Zhang Y1, Aleksandrowicz E1, Gladkich J1, Schönsiegel F1, Herr I1.
• Abstract
• Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis.
Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current
therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and
the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces
apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines
DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated
with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-κB activity, self-
renewal and differentiation potential, and stemcell signaling via spheroid- and colony-forming assays, FACS and
western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after
xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL,
though the agents acted synergistically when applied in combination. This was associated with the inhibition of
TRAIL-induced NF-κB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition;
and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth
were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings
suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains
the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target thecancer-specific
activity of TRAIL in CSCs.

• Sulforaphane inhibits mammary adipogenesis by targeting adipose
mesenchymal stem cells.
• Li Q1, Xia J, Yao Y, Gong DW, Shi H, Zhou Q.
• Abstract
• It is now well accepted that tumor cells actively communicate with the tumor
microenvironment (e.g., adipocytes) leading to the progression of
breast cancer and other malignancies. It is also known that adipose
mesenchymal stem cells (MSCs) have the ability to differentiate into mature
adipocytes and initiate cytokine signaling within the tumor microenvironment.
Here, we examine the role of MSC-differentiated adipocytes on breast cancer cell
migration, and test the effects of sulforaphane (SFN, a dietary chemoprevention
agent) on adipocyte-breast cancer cell interaction. Our results demonstrate that
SFN promotes MSC self-renewal and inhibits adipogenic differentiation.
Subsequently, SFN treatment of adipocytes considerably hinders cytokine
communication with breast cancer cells, thereby decreasing breast cancer cell
migration and tumor formation.

Targeting cancer stem cells with sulforaphane, a
dietary component from broccoli and broccoli sprouts.
• Li Y1, Zhang T.
• Abstract
• Many studies have supported the protective effects of broccoli and broccoli
sprouts against cancer. The chemopreventive properties of sulforaphane, which is
derived from the principal glucosinolate of broccoli and broccoli sprouts, have
been extensively studied. Recent research into the effects
of sulforaphane oncancer stem cells (CSCs) has drawn lots of interest. CSCs are
suggested to be responsible for initiating and maintaining cancer, and to
contribute to recurrence and drug resistance. A number of studies have indicated
that sulforaphane may target CSCs in different types of cancer through modulation
of NF-κB, SHH, epithelial-mesenchymal transition and Wnt/β-catenin pathways.
Combination therapy withsulforaphane and chemotherapy in preclinical settings
has shown promising results. In this article, we focus on the effects
of sulforaphane on CSCs and self-renewal pathways, as well as giving a brief review
of recent human studies using broccoli sprout preparations

Metformin
• Synergistic anti-proliferative effect of metformin and sorafenib on growth of anaplastic thyroid cancer cells and
their stem cells.
• Chen G1, Nicula D1, Renko K2, Derwahl M1.
• Abstract
• Sorafenib, a multikinase inhibitor has recently been approved for the treatment of radio-iodine refractory thyroid
carcinoma. However, toxic side effects may lead to dose reduction. In the present study, we analyzed whether a
combined therapy with metformin may allow a dose reduction of sorafenib without loss of effectiveness at the
same time. In HTh74 anaplastic thyroid carcinoma (ATC) cells and its derived doxorubicin-resistant HTh74Rdox cell
line, the growth inhibitory effect of sorafenib with or withoutmetformin was investigated. Furthermore, an
analysis of cell cycle arrest in response to sorafenib was performed and the ability of a combined treatment to
induce apoptosis was analyzed. In addition, the effects on clonal growth and formation of stem cell-derived
spheres were assayed. The influence of sorafenib and metformin on MAP kinase pathway was investigated by
analysis of ERK phosphorylation. Sorafenib and metformin synergistically inhibited growth of the two
thyroid cancer cell lines, with a more pronounced effect on the doxorubicin-resistant HTh74Rdox cell line. The two
drugs also synergistically decreased sphere formation, which suggested a specific effect on thyroid cancer stem
cells. The addition of metformin enabled a 25% dose reduction of sorafenib without loss of its growth inhibitory
efficacy. Sorafenib and metformin synergistically decreased the proliferation of ATC cell lines and the outgrowth of
their derived cancer stem cells. A combined treatment enabled a significant dose reduction of sorafenib. In
respect to frequent toxic side effects, clinical studies in future should demonstrate whether the addition
ofmetformin may be an advantage in the chemotherapy of patients with radio-iodine-resistant thyroid cancer.

• Metformin repositioning as antitumoral agent: selective antiproliferative effects in human
glioblastoma stem cells, via inhibition of CLIC1-mediated ion current.
• Gritti M1, Würth R2, Angelini M1, Barbieri F2, Peretti M1, Pizzi E1, Pattarozzi A2, Carra E3, Sirito
R4, Daga A3,Curmi PM5, Mazzanti M1, Florio T2.
• Abstract
• Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2
diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular
mechanisms of this effect are unknown. Here we show that chloride intracellular channel-1 (CLIC1)
is a direct target ofmetformin in human glioblastoma cells. Metformin exposure induces
antiproliferative effects in cancerstem cell-enriched cultures, isolated from three individual WHO
grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a
chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is
preferentially active during the G1-S transition via transient membrane
insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This
effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low,
clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative
CLIC1 pore region impairs metformin modulation of channel activity. The lack of drugs
affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We
identified CLIC1 not only as a modulator of cell cycle progression in human
glioblastoma stem cells but also as the main target ofmetformin's antiproliferative activity, paving
the way for novel and needed pharmacological approaches to glioblastoma treatment

Quercetin
• Dietary polyphenol quercetin targets pancreatic cancer stem cells.
• Molecular OncoSurgery, University Hospital Heidelberg and German
Cancer Research Center Heidelberg, Heidelberg, Germany.
• International Journal of Oncology (Impact Factor: 2.77). 09/2010;
37(3):551-61.Source: PubMed
• ABSTRACT According to the cancer stem cell hypothesis the
aggressive growth and early metastasis of pancreatic cancer may
arise through dysregulation of self-renewal of stem cells in the
tissue. Since recent data suggest targeting of cancer stem cells by
some dietary agents we studied the effect of quercetin, a major
polyphenol and flavonoid commonly detected in many fruits and
vegetables. Using in vitro and in vivo

Dietary polyphenol quercetin targets
pancreatic cancer stem cells
• Authors:
– Wei Zhou
– :
– Ingrid Herr [ i.herr@dkfz.de ]
• View Affiliations
• Published online on: Wednesday, September 1, 2010
• Pages: 551-561
• DOI: 10.3892/ijo_00000704
• Abstract
• According to the cancer stem cell hypothesis the aggressive growth and early metastasis of pancreatic cancer may
arise through dysregulation of self-renewal of stem cells in the tissue. Since recent data suggest targeting of
cancer stem cells by some dietary agents we studied the effect of quercetin, a major polyphenol and flavonoid
commonly detected in many fruits and vegetables. Using in vitro and in vivo models of pancreatic cancer stem
cells we found quercetin-mediated reduction of self-renewal as measured by spheroid and colony formation.
Quercetin diminished ALDH1 activity and reverted apoptosis resistance as detected by substrate assays, FACS and
Western blot analysis. Importantly, combination of quercetin with sulforaphane, an isothiocyanate enriched in
broccoli, had synergistic effects. Although quercetin led to enhanced binding of the survival factor NF-κB, co-
incubation with sulforaphane completely eliminated this pro-proliferative feature. Moreover, quercetin prevented
expression of proteins involved in the epithelial-mesenchymal transition, which was even stronger in presence of
sulforaphane, suggesting the blockade of signaling involved in early metastasis. In vivo, quercetin inhibited growth
of cancer stem cell-enriched xenografts associated with reduced proliferation, angiogenesis, cancer stem cell-
marker expression and induction of apoptosis. Co-incubation with sulforaphane increased these effects and no
pronounced toxicity on normal cells or mice was observed. Our data suggest that food ingredients complement
each other in the elimination of cancer stem cell-characteristics. Since carcinogenesis is a complex process,
combination of bioactive dietary agents with complementary activities may be most effective.

The dietary bioflavonoid quercetin synergizes with epigallocathechin gallate
(EGCG) to inhibit prostate cancer stem cell characteristics, invasion,
migration and epithelial-mesenchymal transition
• Su-Ni Tang1, Chandan Singh2, Dara Nall2, Daniel Meeker1, Sharmila Shankar2 and Rakesh K Srivastava1*
• *Corresponding author: Rakesh K Srivastava rsrivastava@kumc.edu
• Author Affiliations
• 1Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Cancer Center, The University of Kansas Medical
Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA
• Background
• Much attention has been recently focused on the role of cancer stem cells (CSCs) in the initiation and progression of solid malignancies. Since CSCs
are able to proliferate and self-renew extensively due to their ability to express anti-apoptotic and drug resistant proteins, thus sustaining tumor
growth. Therefore, the strategy to eradicate CSCs might have significant clinical implications. The objectives of this study were to examine the
molecular mechanisms by which epigallocathechin gallate (EGCG) inhibits stem cell characteristics of prostate CSCs, and synergizes with quercetin, a
major polyphenol and flavonoid commonly detected in many fruits and vegetables.
• Results
• Our data indicate that human prostate cancer cell lines contain a small population of CD44+CD133+cancer stem cells and their self-renewal capacity is
inhibited by EGCG. Furthermore, EGCG inhibits the self-renewal capacity of CD44+α2β1+CD133+ CSCs isolated from human primary prostate tumors,
as measured by spheroid formation in suspension. EGCG induces apoptosis by activating capase-3/7 and inhibiting the expression of Bcl-2, survivin
and XIAP in CSCs. Furthermore, EGCG inhibits epithelial-mesenchymal transition by inhibiting the expression of vimentin, slug, snail and nuclear β-
catenin, and the activity of LEF-1/TCF responsive reporter, and also retards CSC's migration and invasion, suggesting the blockade of signaling
involved in early metastasis. Interestingly, quercetin synergizes with EGCG in inhibiting the self-renewal properties of prostate CSCs, inducing
apoptosis, and blocking CSC's migration and invasion. These data suggest that EGCG either alone or in combination with quercetin can eliminate
cancer stem cell-characteristics.
• Conclusion
• Since carcinogenesis is a complex process, combination of bioactive dietary agents with complementary activities will be beneficial for prostate
cancer prevention and/ortreatment.

• Role of Flavonoids in Future Anticancer Therapy by Eliminating the Cancer Stem Cells.
• Sak K1, Everaus H.
• Abstract
• Despite the numerous recent advances made in conventional anticancer therapies, metastasis and
recurrence still remain the major problems in cancer management. The current treatment
modalities kill the bulk of the tumor, leaving cancer stem cells behind and therefore, the agents
specifically targeting thiscancer initiating cell population may have important clinical implications.
In this review article, the data about the inhibitory action of flavonoids, both natural as well as their
synthetic derivatives, on the self-renewal capacity and survival of cancer stem cells of different
origins are compiled and analyzed. These data indicate that several plant secondary metabolites,
including soy isoflavone genistein, green tea catechins and a widely distributed flavonol quercetin,
have the potential to suppress the stemness markers and properties, traits of the epithelial-to-
mesenchymal transition and migratory characteristics, being also able to sensitize these cells to the
standard chemotherapeutic drugs. These polyphenolic compounds act through multiple signal
transduction pathways, providing thus the maximal therapeutic response and offering some
promise to be included in the future cancer treatment schemes in combination with the
conventional therapies. Such approach may give an important contribution to the shift
of cancermanagement from palliative to curative mode, likely leading to the disease-free survival.
Thus, flavonoids can serve as attractive candidates for novel anticancer agents by eliminating the
roots of cancer.

Resveratrol
Semilla de Uva
• Differential contribution of ROS to resveratrol-induced cell death and loss of self-renewal capacity of
ovarian cancer stem cells.
• Seino M1, Okada M2, Shibuya K3, Seino S4, Suzuki S5, Takeda H6, Ohta T7, Kurachi H8, Kitanaka C9.
• Abstract
• BACKGROUND/AIM:
• Cancer stem cells (CSCs) are considered to contribute to the poor prognosis of ovarian cancer as a major cause of
fatal recurrence. Identification of effective measures to eliminate ovarian CSCs through induction of cell death
and/or loss of self-renewal capacity would, therefore, be key to successful management of ovarian cancer.
• MATERIALS AND METHODS:
• The effects of resveratrol on the viability and self-renewal capacity of CSCs derived from A2780 human
ovarian cancer cells were examined. The involvement of reactive oxygen species (ROS) was also investigated.
• RESULTS:
• At a non-toxic to normal human fibroblasts concentration, resveratrol effectively killed ovarian CSCs independently
of ROS, while ROS-dependently impaired the self-renewal capacity of ovarian CSCs that
survived resveratrol treatment.
• CONCLUSION:
• Our findings not only shed light on a novel mechanism of action for resveratrol but also suggest that resveratrol,
or its analogs, may be useful for CSC-directed therapy against ovarian cancer.
• Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Resveratrol Inhibits Pancreatic Cancer Stem Cell Characteristics in Human
and KrasG12D Transgenic Mice by Inhibiting Pluripotency Maintaining Factors
and Epithelial-Mesenchymal Transition
• Abstract
• Background
• Cancer stem cells (CSCs) can proliferate and self-renew extensively due to their ability to express anti-apoptotic
and drug resistant proteins, thus sustaining tumor growth. Therefore, the strategy to eradicate CSCs might have
significant clinical implications. The objectives of this study were to examine the molecular mechanisms by which
resveratrol inhibits stem cell characteristics of pancreatic CSCs derived from human primary tumors and
KrasG12Dtransgenic mice.
• Methodology/Principal Findings
• Human pancreatic CSCs (CD133+CD44+CD24+ESA+) are highly tumorigenic and form subcutaneous tumors in
NOD/SCID mice. Human pancreatic CSCs expressing high levels of CD133, CD24, CD44, ESA, and aldehyde
dehydrogenase also express significantly more Nanog, Oct-4, Notch1, MDR1 and ABCG2 than normal pancreatic
tissues and primary pancreatic cancer cells. Similarly, CSCs from KrasG12D mice express significantly higher levels of
Nanog and Oct-4 than pancreatic tissues from Pdx-Cre mice. Resveratrol inhibits the growth (size and weight) and
development (PanIN lesions) of pancreatic cancer in KrasG12D mice. Resveratrol inhibits the self-renewal capacity of
pancreatic CSCs derived from human primary tumors and KrasG12D mice. Resveratrol induces apoptosis by
activating capase-3/7 and inhibiting the expression of Bcl-2 and XIAP in human CSCs. Resveratrol inhibits
pluripotency maintaining factors (Nanog, Sox-2, c-Myc and Oct-4) and drug resistance gene ABCG2 in CSCs.
Inhibition of Nanog by shRNA enhances the inhibitory effects of resveratrol on self-renewal capacity of CSCs.
Finally, resveratrol inhibits CSC's migration and invasion and markers of epithelial-mesenchymal transition (Zeb-1,
Slug and Snail).
• Conclusions/Significance
• These data suggest that resveratrol inhibits pancreatic cancer stem cell characteristics in human and
KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. In
conclusion, resveratrol can be used for the management of pancreatic cancer.

Oleuropeína
Hoja de OLiva
• Olea europaea leaf extract improves the treatment response of GBM stem cells by modulating
miRNA expression
• Abstract
• The stem-like cells of Glioblastoma multiforme (GBM) tumors (GSCs) are one of the important
determinants of recurrence and drug resistance. The aims of the current study were to evaluate the
anticancer effect ofOlea europaea leaf extract (OLE) on GBM cell lines, the association between
OLE and TMZ responses, and the effect of OLE and the OLE-TMZ combination in GSCs and to clarify
the molecular mechanism of this effect on the expression of miRNAs related to cell death. The anti-
proliferative activity of OLE and the effect of the OLE-TMZ combination were tested in the T98G, U-
138MG and U-87MG GBM cell lines using WST-1 assay. The mechanism of cell death was analyzed
with Annexin V/FITC and TUNEL assays. The effects of OLE on the expression levels of miR-181b,
miR-153, miR-145 and miR-137 and potential mRNA targets were analyzed in GSCs using RT-qPCR.
OLE exhibited anti-proliferative effects via apoptosis and necrosis in the GBM cell lines. In addition,
OLE significantly induced the expression of miR-153, miR-145, and miR-137 and decreased the
expression of the target genes of these miRNAs in GSCs (p < 0.05). OLE causes cell death in GBM
cells with different TMZ responses, and this effect is synergistically increased when the cells are
treated with a combination of OLE and TMZ. This is the first study to indicate that OLE may interfere
with the pluripotency of GSCs by modulating miRNA expression. Further studies are required, but
we suggest that OLE may have a potential for advanced therapeutic cancer drug studies in GBM

Emodin
Cáscara de la Sábila
• Emodin as an effective agent in targeting cancer stem-like side population cellsof gallbladder carcinoma.
• Li XX1, Dong Y, Wang W, Wang HL, Chen YY, Shi GY, Yi J, Wang J.
• Abstract
• Side population (SP) cells are previously identified from bone marrow based on their capacity to efflux of the
fluorescent dye Hoechst 33342. Recent studies demonstrate that SP cells isolated from variouscancer cell lines and
primary tumors possess stem-cell-like properties. Thus, targeting tumor SP cellsmay provide new strategies for
treatment in clinic. We previously showed that 1,3,8-trihydroxy-6-methylanthraquinone (emodin), a reactive
oxygen species (ROS) generator, enhanced sensitivity of gallbladder cancer SGC-996 cells to cisplatin (CDDP) via
generation of ROS and downregulation of multidrug-resistance-associated protein 1 (MRP1). To determine
whether emodin also acts effectively oncancer stem cells of gallbladder carcinoma, we use SP cells as a model
of cancer stem-cell-like cells. Here, we found that emodin, via ROS-related mechanism and suppressing the
function of ATP-binding cassette super-family G member (ABCG2), which is known to be associated with Hoechst
dye efflux activity of SP cells, not only reduced the ratio, inhibited clone formation, and eliminated sphere
formation of SP cells effectively, but also promoted obviously the intracellular accumulation of doxorubicin, the
main substrate of the efflux pump ABCG2. In addition, emodin could sensitize CDDP, via inhibition of expression of
ABCG2, to overcome chemoresistance of SP cells. Importantly, similar to the experiment in vitro, emodin/CDDP co-
treatment in vivo suppressed the tumor growth derived from SP cells through downregulating ABCG2 expression.
Our results suggest that emodin is an effective agent targeting cancerstem-like SP cells of gallbladder carcinoma,
either alone or acts as a chemotherapy enhancer.

• Emodin Suppresses Maintenance of Stemness by Augmenting Proteosomal Degradation of
Epidermal Growth Factor Receptor/Epidermal Growth Factor Receptor Variant III in
Glioma Stem Cells.
• Kim J1, Lee JS, Jung J, Lim I, Lee JY, Park MJ.
• Abstract
• There is a growing body of evidence that small subpopulations of cells with stem cell-like
characteristics within most solid tumors are responsible for the malignancy of
aggressive cancer cells and that targeting these cells might be a good therapeutic strategy to reduce
the risk of tumor relapse after therapy. Here, we examined the effects of emodin (1,3,8-trihydroxy-
6-methylanthraquinone), an active component of the root and rhizome of Rheum palmatum that
has several biological activities, including antitumor effects, on primary cultured
glioma stem cells (GSCs). Emodin inhibited the self-renewal activity of GSCs in vitro as evidenced by
neurosphere formation, limiting dilution, and soft agar clonogenic assays. Emodin inhibited the
maintenance of stemness by suppressing the expression of Notch intracellular domain,
nonphosphorylated β-catenin, and phosphorylated STAT3 proteins. In addition, treatment
with emodinpartially induced apoptosis, reduced cell invasiveness, and sensitized GSCs to ionizing
radiation. Intriguingly, emodin induced proteosomal degradation of epidermal growth factor
receptor (EGFR)/EGFR variant III (EGFRvIII) by interfering with the association of EGFR/EGFRvIII with
heat shock protein 90, resulting in the suppression of stemness pathways. Based on these data, we
propose that emodin could be considered as a potent therapeutic adjuvant that targets GSCs.

Antocianina
• The polyphenolic-rich Aronia melanocarpa juice kills teratocarcinomal cancer stem-like cells, but not their
differentiated counterparts
• Highlights
• •Aronia melanocarpa juice (AMJ) kills embryonal carcinoma (EC) stem cells.
• •AMJ has no effect on normal restricted pluripotent stem cells (i.e. fibroblasts).
• •AMJ has no effect on differentiated EC cells.
• •The selective pro-apoptotic activity of AMJ explains its chemopreventive properties.
• •The activation of the pro-apoptotic signalling pathway by AMJ is p53/p73-dependent.
• Abstract
• A diet rich in plant-derived products is expected to have anticancer chemopreventive effects by acting on the
appearance and growth of cancer stem cells (CSCs). Thus the effects of Aronia melanocarpa juice (AMJ) on the
mouse embryonal carcinoma (EC) stem cell line P19 were investigated. AMJ inhibited cell proliferation, induced
cell cycle arrest in S phase and triggered apoptosis. A pronounced upregulation of tumour suppressors p53 and
p73 was observed in association with caspase-3 activation and a downregulation of the anti-apoptotic protein
UHRF1 and the stemness factor Oct-4. Overall the results strongly suggest that AMJ is functionally able to
counteract the carcinogenesis process by targeting CSCs. Interestingly AMJ selectively kills undifferentiated EC
cells, without significant effects on normal restricted pluripotent cells (i.e. NIH/3T3 fibroblasts) or even
differentiated EC cells. This argues that a differentiation therapy might normalize the pathological phenotype of a
CSC which becomes insensitive to further plant-derived pharmacological treatment.
• Analysis of polyphenols in chokeberries has identified the following individual chemicals (among hundreds known
to exist in the plant kingdom): cyanidin-3-galactoside, cyanidin-3-arabinoside, quercetin-3-
glycoside, epicatechin, caffeic acid, delphinidin, petunidin, pelargonidin, peonidin, and malvidin.[20][22][27] All these
except caffeic acid are members of the flavonoid category of phenolics

Natural Grape Extracts Regulate
Colon Cancer Cells Malignancy.
• Signorelli P1, Fabiani C, Brizzolari A, Paroni R, Casas J, Fabriàs G, Rossi D, Ghidoni R, Caretti A.
• Abstract
• Natural dietary components are evolutionary-selected molecules able to control inflammation and
cancerous transformation and progression. Because many studies assessed the beneficial
properties of key molecules extracted from grapes, we aimed at investigating the properties of
Liofenol™, a natural red wine lyophilized extract, devoid of alcohol and composed by a
miscellaneous of components (polyphenols, flavonoids, anthocyanins). We proved that the
colon cancer cell line HCT116 responded to Liofenol™ treatment by reducing their proliferation, in
association with an increase of p53 and p21 cell cycle gate keepers. Liofenol™ increased
dihydroceramides, sphingolipid mediators involved in cell cycle arrest and reduced proliferation
rate. We observed a strong induction of antioxidant response, with the activation of the
transcriptional factor Nrf2, involved in redox homeostasis and differentiation, without altering
tumor sensitivity to chemotherapy. Liofenol™ induced an important morphology change in
HCT116 cells, migration inhibition, undifferentiated stem/stem-like cells markers downregulation,
and E-cadherin downregulation, interested in epithelia to mesenchymal malignant transition. We
conclude that lyophilized grape extract, at dose comparable to putative dietary doses, can activate
molecular pathways, involving Nrf2 signaling and the modulation of structural and signaling
sphingolipid mediators that cooperate in promoting differentiation and reducing proliferation of
digestive tract cancer cells.

FIN
Gracias
www.avantari.com
sbarrio@avantari.com

Diferenciación de Células Madre de
Cáncer.
• Una caracteristica primaria de las CM de cancer es su habilidad a
diferenciarse en celulas heterogeneas con diferentes grados de
proliferación.
• Beta caroteno-> Acido Retinoico-> rol critico en embryogenisis y
hematopoiesis.
• Acido retinoico es un potente promotor para terapia de diferenciación.
• Leucemia aguda promielocitica, es causada por una translocacion
cromosomica, que produce una proteina quimerica, entre AR y el
receptor alfa, y una proteina llamada proteina de Leucemia promielocitica.
Al añadir AR se induce la maduracion de celulas de Leucemia
promielociticas a Neutrofilos. Como terapia adyudante, el AR
dramticamente mejora al paciente, con indices de remision del 90% y
sobrevivencia a largo plazo del 75% delos pacientes.

Novel strategies targeting cancer stem
cells through phytochemicals and their analogs.
• Dandawate P1, Padhye S, Ahmad A, Sarkar FH.
• Abstract
• Cancer stem cells (CSCs) are cells that exist within a tumor with a capacity of self-
renewal and an ability to differentiate, giving rise to heterogeneous populations
of cancer cells. These cells are increasingly being implicated in resistance to
conventional therapeutics and have also been implicated in tumor recurrence.
Several cellular signaling pathways including Notch, Wnt, phosphoinositide-3-
kinase-Akt-mammalian target of rapamycin pathways, and known markers such as
CD44, CD133, CD166, ALDH, etc. have been associated with CSCs. Here, we have
reviewed our current understanding of self-renewal pathways and factors that
help in the survival of CSCs with special emphasis on those that have been
documented to be modulated by well characterized natural agents such as
curcumin, sulforaphane, resveratrol, genistein, and epigallocatechin gallate. With
the inclusion of a novel derivative of curcumin, CDF, we showcase how natural
agents can be effectively modified to increase their efficacy, particularly against
CSCs. We hope that this article will generate interest among researchers for
further mechanistic and clinical studies exploiting the cancer preventive and
therapeutic role of nutraceuticals by targeted elimination of CSCs

Induction of murine embryonic stem cell
differentiation by medicinal plant extracts.
• Reynertson KA1, Charlson ME, Gudas LJ.
• Abstract
• Epidemiological evidence indicates that diets high in fruits and vegetables provide a measure
of cancer chemoprevention due to phytochemical constituents. Natural products are a rich source
of cancerchemotherapy drugs, and primarily target rapidly cycling tumor cells. Increasing evidence
indicates that many cancers contain small populations of resistant, stem-like cells that have the
capacity to regenerate tumors following chemotherapy and radiation, and have been linked to the
initiation of metastases. Our goal is to discover natural product-based clinical or dietary
interventions that selectively target cancer stem cells, inducing differentiation. We adapted an
alkaline phosphatase (AP) stain to assay plant extracts for the capacity to induce differentiation in
embryonic stem (ES) cells. AP is a characteristic marker of undifferentiated ES cells, and this
represents a novel approach to screening medicinal plant extracts. Following a survey of
approximately 100 fractions obtained from 12 species of ethnomedically utilized plants, we found
fractions from 3 species that induced differentiation, decreasing AP and transcript levels of
pluripotency markers (Nanog, Oct-4, Rex-1). These fractions affected proliferation of murine ES, and
human embryonal, prostate, and breast carcinoma cells in a dose-dependent manner. Several
phytochemical constituents were isolated; the antioxidant phytochemicals ellagic acid and
gallic acid were shown to affect viability of cultured breast carcinoma cell

Green Tea
• Epigallocathechin gallate, polyphenol present in green tea, inhibits stem-like characteristics and epithelial-mesenchymal transition in
nasopharyngeal cancer cell lines.
• Lin CH1, Shen YA, Hung PH, Yu YB, Chen YJ.
• Abstract
• BACKGROUND:
• Previous studies have demonstrated that the consumption of green tea inhibits the growth of various cancers. Most cancers are believed to be
initiated from and maintained by a small population of cancer stem-like cells (CSC) or tumor-initiating cells (TIC) that are responsible for tumor
relapse and chemotherapeutic resistance. Although epigallocathechin gallate (EGCG), the most abundant catechin in green tea, has been reported to
induce growth inhibition and apoptosis in some cancer cells, its effect on CSC is undefined. In this study, we enriched CSC by the sphere formation,
and provided an efficient model for further experiments. Using this method, we examined the effects of EGCG regulating the nasopharyngeal
carcinoma (NPC) CSC and attempted to elucidate the possible mechanisms.
• METHODS:
• NPC TW01 and TW06 cell lines were enriched by sphere formation and characterized their phenotypical properties, such as invasion capacity,
epithelial-mesenchymal transition (EMT) and gene expression were analyzed by quantitative real-time reverse transcription polymerase chain
reaction (q-RT-PCR). EGCG-induced growth inhibition in the parental and sphere-derived cells was determined by MTT and bromodeoxyuridine
(BrdU) assay. EGCG-induced apoptosis was analyzed by flow cytometry with Annexin V and PI staining. The effects of EGCG on sphere-derived cell
tumorigenicity, migration and invasion were determined by soft agar assay, wound healing, and cell invasion assay. The alternation of protein
expression regulated by EGCG on these sphere-derived cells was assessed by immunofluorescence staining and western blot.
• RESULTS:
• NPC sphere-derived cells grown in serum-free non-adherent culture showed increased expression of stem cell markers and EMT markers compared
to parental cells grown in conventional culture. Although EGCG induced growth inhibition and apoptosis in the parental cells in a dose-dependent
manner, it was not as effective against spheres. However, EGCG potently inhibited sphere formation and can eliminate the stem cell characteristics
of NPC and inhibit the epithelial-mesenchymal transition (EMT) signatures.
• CONCLUSIONS:
• Overall, these findings show that NPC cells with sphere formations possess the properties of CSC. Using this model, we found that EGCG regulated
NPC CSC, their self-renewal capacity, and inhibited their invasive characteristics. It supports the pivotal role of EGCG as a dietary compound targeting
NPC and may decrease recurrence and metastasis in nasopharyngeal carcinoma cell

Curcumin
• Curcumin and Cancer Stem Cells: Curcumin Has
Asymmetrical Effects on Cancer and Normal Stem Cells.
• Sordillo PP1, Helson L2.
• Abstract
• Curcumin has been shown to have numerous cytotoxic
effects on cancer stem cells (CSCs). This is due to its
suppression of the release of cytokines, particularly
interleukin (IL)-6, IL-8 and IL-1, which stimulate CSCs, and
also to its effects at multiple sites along CSC pathways, such
as Wnt, Notch, Hedgehog and FAK. In spite of its multiple
actions targeting CSCs, curcumin has little toxicity against
normal stem cells(NSCs). This may be due to curcumin's
different effects on CSCs and NSCs.

Curcumin and Cancer Stem Cells: Curcumin Ηas
Asymmetrical Effects on Cancer and Normal Stem Cells
• Abstract. Curcumin has been shown to have numerous cytotoxic effects on cancer stem cells
(CSCs). This is due to its suppression of the release of cytokines, particularly interleukin (IL)-6, IL-8
and IL-1, which stimulate CSCs, and also to its effects at multiple sites along CSC pathways, such as
Wnt, Notch, Hedgehog and FAK. In spite of its multiple actions targeting CSCs, curcumin has little
toxicity against normal stem cells (NSCs). This may be due to curcumin’s different effects on CSCs
and NSCs. The use of cytotoxic therapies remains the standard treatment for patients with
metastatic cancer. The efficacy of these treatments is limited, with recurrence common. According
to the cancer stem cell paradigm, cancers contain distinct subpopulations of cancer
stem/progenitor cells (CSCs) characterized by self-renewal mechanisms and resistance to
conventional treatments (1-3). When CSCs are transferred to an immune-deficient mouse, these
cells can reconstitute the original cancer in the animal (4-6). Even a small number of stem cells (as
few as 100) can be effective in bringing about the transplantation (7). However, tumors depleted of
stem cells do not grow as xenografts (8). These CSCs have been shown to be resistant to
chemotherapy (9), radiation (10) and hormone therapy (11). For this reason, metastases from solid
tumors, in particular, will re-appear even after initially successful treatments and prolonged periods
of complete remission. Further, an unintended consequence of induced cancer cell death is the
release of inflammatory cytokines, which can stimulate replication of CSCs (12-14). The percentage
of CSCs in the cancer has been shown to increase in patients receiving neoadjuvant chemotherapy
(9, 15, 16). Thus, an “equilibrium” may be formed where chemotherapy-induced tumor cell death
results in increased stimulation of tumor growth (12). In addition, the cytokines secreted during
induced cancer cell death can result in resistance to cytotoxic agents, so that metastases, when
they occur, may be refractory to therapy (14, 17, 18). This suggests, for therapy to be effective on a
consistent basis, it must eliminate both CSCs and non-stem cell cancer cell

Curcumin inhibits breast cancer stem cell migration by
amplifying the E-cadherin/beta-catenin negative feedback
loop.
• Mukherjee S, Mazumdar M, Chakraborty S, Manna A, Saha S, Khan P, Bhattacharjee P, Guha D, Adhikary
A,Mukhjerjee S, Das T.
• Abstract
• INTRODUCTION:
• The existence of cancer stem cells (CSCs) has been associated with tumor initiation, therapy-resistance, tumor
relapse, angiogenesis and metastasis. Curcumin, a plant ployphenol, has several anti-tumor effects and has been
shown to target CSCs. Here, we aimed at evaluating (i) the mechanisms underlying the aggravated migration
potential of breast CSCs (bCSCs), and (ii) the effects ofcurcumin in modulating the same.
• METHODS:
• The migratory behaviour of MCF-7 bCSCs was assessed using cell adhesion, spreading, transwell-migration and 3D-
invasion assays. Stem cell characteristics were studied using flow cytometry. The effects of curcumin on bCSCs
were deciphered by cell viability assay, western blotting, confocal microscopy and si-RNA mediated gene-silencing.
Evaluations of breast cancer patient samples were performed using immunohistochemistry and flow cytometry.
• RESULTS:
• Here we report that bCSCs are endowed with aggravated migration property due to the inherent suppression of
the tumor suppressor, E-cadherin, which is restored by curcumin. A search for the underlying mechanism revealed
that in bCSCs, higher nuclear translocation of beta-catenin (i) decreases E-cadherin/beta-catenin complex
formation and membrane retention of beta-catenin, (ii) up-regulates the expression of its EMT-promoting target
genes including Slug, thereby (iii) down-regulating E-cadherin transcription to subsequently promote EMT and
migration of these bCSCs. In contrast, curcumin inhibits beta-catenin nuclear translocation thus impeding trans-
activation of Slug. As a consequence, E-cadherin expression is restored thereby increasing E-cadherin/beta-catenin
complex formation and cytosolic retention of more beta-catenin to finally suppress EMT and migration of bCSCs.
• CONCLUSIONS:
• Cumulatively, our findings disclose that curcumin inhibits bCSC migration by amplifying E-cadherin/beta-catenin
negative feedback loop.

Curcumin suppresses crosstalk between colon cancer
stem cells and stromal fibroblasts in the tumor
microenvironment: potential role of EMT
• .
• Buhrmann C1, Kraehe P1, Lueders C2, Shayan P3, Goel A4, Shakibaei M1.
• Abstract
• OBJECTIVE:
• Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk
between colorectal cancer (CRC) cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU), especially
on cancerstem cell (CSC) survival in a 3D-co-culture model that mimics in vivo tumor microenvironment.
• METHODS:
• Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro
with/without curcumin and/or 5-FU.
• RESULTS:
• Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancercells and fibroblasts and enhanced up-regulation of
metastatic active adhesion molecules (β1-integrin, ICAM-1), transforming growth factor-β signaling molecules (TGF-β3, p-Smad2), proliferation
associated proteins (cyclin D1, Ki-67) and epithelial-to-mesenchymal transition (EMT) factor (vimentin) in HCT116 compared with tumor mono-
cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13), TGF-β3, favored CSC
survival (characterized by up-regulation of CD133, CD44, ALDH1) and EMT-factors (increased vimentin and Slug, decreased E-cadherin) in HCT116
compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but
dramatically decreased in the presence ofcurcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET), thereby sensitizing
CSCs to 5-FU treatment.
• CONCLUSION:
• Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor
microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-
β and EMT. Modulation of this synergistic crosstalk by curcumin might be a potential therapy for CRC and suppress metastasis.

Curcumin targets breast cancer stem-
like cells with microtentacles that persist in
mammospheres and promote reattachment.
• Charpentier MS1, Whipple RA, Vitolo MI, Boggs AE, Slovic J, Thompson KN, Bhandary L, Martin SS.
• Abstract
• Cancer stem-like cells (CSC) and circulating tumor cells (CTC) have related properties associated
with distant metastasis, but the mechanisms through which CSCs promote metastasis are unclear.
In this study, we report that breast cancer cell lines with more stem-like properties display higher
levels of microtentacles (McTN), a type of tubulin-based protrusion of the plasma cell membrane
that forms on detached or suspended cells and aid in cell reattachment. We hypothesized that CSCs
with large numbers of McTNs would more efficiently attach to distant tissues, promoting metastatic
efficiency. The naturally occurring stem-like subpopulation of the human mammary epithelial
(HMLE) cell line presents increased McTNs compared with its isogenic non-stem-like subpopulation.
This increase was supported by elevated α-tubulin detyrosination and vimentin protein levels and
organization. Increased McTNs in stem-like HMLEs promoted a faster initial reattachment of
suspended cells that was inhibited by the tubulin-directed drug, colchicine, confirming a functional
role for McTNs in stem cell reattachment. Moreover, live-cell confocal microscopy showed that
McTNs persist in breast stem cell mammospheres as flexible, motile protrusions on the surface of
the mammosphere. Although exposed to the environment, they also function as extensions
between adjacent cells along cell-cell junctions. We found that treatment with the breast CSC-
targeting compound curcumin rapidly extinguished McTN in breast CSC, preventing reattachment
from suspension. Together, our results support a model in which breast CSCs with cytoskeletal
alterations that promote McTNs can mediate attachment and metastasis but might be targeted
by curcumin as an antimetastatic strategy

The generation of induced pluripotent stem cells for macular
degeneration as a drug screening platform: identification
of curcumin as a protective agent for retinal pigment
epithelial cells against oxidative stress.
• Chang YC1, Chang WC2, Hung KH3, Yang DM4, Cheng YH5, Liao YW4, Woung LC6, Tsai CY6, Hsu CC7, Lin
TC7,Liu JH8, Chiou SH9, Peng CH10, Chen SJ7.
• Abstract
• Age-related macular degeneration (AMD) is one retinal aging process that may lead to irreversible
vision loss in the elderly. Its pathogenesis remains unclear, but oxidative stress inducing retinal
pigment epithelial (RPE) cells damage is perhaps responsible for the aging sequence of retina and
may play an important role in macular degeneration. In this study, we have reprogrammed
T cells from patients with dry type AMD into induced pluripotent stem cells (iPSCs) via integration-
free episomal vectors and differentiated them into RPE cells that were used as an expandable
platform for investigating pathogenesis of the AMD and in-vitro drug screening. These patient-
derived RPEs with the AMD-associated background (AMD-RPEs) exhibited reduced antioxidant
ability, compared with normal RPE cells. Among several screened candidate drugs, curcumin caused
most significant reduction of ROS in AMD-RPEs. Pre-treatment of curcumin protected these AMD-
RPEs from H2O2-induced cell death and also increased the cytoprotective effect against the
oxidative stress of H2O2 through the reduction of ROS levels. In addition,curcumin with its versatile
activities modulated the expression of many oxidative stress-regulating genes such as PDGF, VEGF,
IGFBP-2, HO1, SOD2, and GPX1. Our findings indicated that the RPE cellsderived from AMD patients
have decreased antioxidative defense, making RPE cells more susceptible to oxidative damage and
thereby leading to AMD formation. Curcumin represented an ideal drug that can effectively restore
the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for
macular degeneration therapy and an agent against aging-associated oxidative stress

Curcumin enhances the effectiveness of cisplatin by
suppressing CD133+ cancer stem cells in laryngeal carcinoma
treatment.
• Zhang H1, Yu T, Wen L, Wang H, Fei D, Jin C.
• Abstract
• Chemoresistance is one of the major barriers to chemotherapeutic treatment and
it has been established that CD133+ cancer stem cells are responsible for drug
resistance in laryngeal carcinoma. In the present study, curcumin and cisplatin
were used as a combined treatment to induce the sensitivity of CD133+cancer
stem cells to chemotherapeutic agents and to enhance therapeutic effectiveness.
The results revealed that in untreated and cisplatin-treated HEp-2 cell groups, the
percentage of CD133+ cells was 4.50 and 6.89%, respectively. However, in the
combined treatment group, the percentage of CD133+ cellswas markedly reduced
to 1.49%, indicating that curcumin may increase the sensitivity of CD133+ cells to
cisplatin, leading to the suppression of chemoresistance in HEp-2 cells.
Furthermore, the expression of ATP-binding cassette sub-family G member 2
(ABCG2), which is an important gene for chemoresistance, was demonstrated to
be reduced in CD133+ cancer stem cells following combined treatment. These
results suggest that the combined application of curcumin with chemotherapeutic
drugs may be a reliable and effective approach for the treatment of laryngeal
carcinoma.

Ellagic acid
• Abstract

• Abstract

• Effect of ellagic acid on proliferation, cell adhesion and apoptosis in SH-SY5Y
human neuroblastoma cells.
• Fjaeraa C1, Nånberg E.
• Abstract
• Ellagic acid, a polyphenolic compound found in berries, fruits and nuts, has been
shown to possess growth-inhibiting and apoptosis promoting activities
in cancer cell lines in vitro. The objective of this study was to investigate the effect
of ellagic acid in human neuroblastoma SH-SY5Y cells. In cultures of SH-
SY5Y cells incubated with ellagic acid, time- and concentration-dependent
inhibitory effects on cell number were demonstrated. Ellagic acid induced cell
detachment, decreased cell viability and induced apoptosis as measured by DNA
strand breaks. Ellagic acid-induced alterations in cell cycle were also observed.
Simultaneous treatment with all-trans retinoic acid did not rescue
the cells from ellagic acid effects. Furthermore, the results suggested that pre-
treatment with all-trans retinoic acid to induce differentiation and cell cycle arrest
did not rescue the cells from ellagic acid-induced cell death.

Colon
• Colon carcinogenesis: influence of Western diet-induced obesity and targeting stem cells using
dietary bioactive compounds.
• Kasdagly M1, Radhakrishnan S2, Reddivari L3, Veeramachaneni DN4, Vanamala J5.
• Abstract
• Colon cancer strikes more than 1 million people annually and is responsible for more than
500,000 cancerdeaths worldwide. Recent evidence suggests that the majority of malignancies,
including colon cancer are driven by cancer stem cells (CSCs) that are resistant to current
chemotherapeutic approaches leading tocancer relapse. Wnt signaling plays a critical role in
colon stem cell renewal and carcinogenesis. Leucine-rich repeat-containing G protein-coupled
receptor 5 (LGR5), a Wnt target gene, and aldehyde dehydrogenase 1 B1 (ALDH1B1) are good
markers for normal and malignant human colon stem cells. Diet contributes to 20% to 42% of all
human cancers and 50% to 90% of colon cancer. Recent evidence shows that the Western diet has a
causative link to colon cancer; however, mechanisms of action are not fully elucidated. Western
diet-induced obesity elevates systemic insulin-like growth factor-1 and insulin levels, which could
lead to elevated proliferation and suppressed apoptosis of CSCs through PI3K/AKT/Wnt pathway.
Although conventional chemotherapy targets the PI3K/AKT pathways and can significantly reduce
tumor size, it fails to eliminate CSCs and has serious side effects. Dietary bioactive compounds such
as grape seed extract, curcumin, lycopene, and resveratrol have promising chemopreventive
effects, without serious side effects on various types of cancers due to their direct and indirect
actions on CSC self-renewal pathways such as the Wnt pathway. Understanding the role of CSCs in
diet-induced coloncancer will aid in development of evidence-based dietary chemopreventive
strategies and/or therapeutic agents targeting CSCs.

Sulforaphane
• Sulforaphane and TRAIL induce a synergistic elimination of advanced prostate cancer stem-like cells.
• Labsch S1, Liu L1, Bauer N1, Zhang Y1, Aleksandrowicz E1, Gladkich J1, Schönsiegel F1, Herr I1.
• Abstract
• Advanced androgen-independent prostate cancer (AIPC) is an aggressive malignancy with a poor prognosis.
Apoptosis-resistant cancer stem cells (CSCs) have been identified in AIPC and are not eliminated by current
therapeutics. Novel therapeutic options, which are currently being evaluated in patient studies, include TRAIL and
the broccoli-derived isothiocyanate sulforaphane. Although neither agent targets normal cells, TRAIL induces
apoptosis in most cancer cells, and sulforaphane eliminates CSCs. In this study, the established AIPC cell lines
DU145 and PC3, with enriched CSC features, and primary patient-derived prostate CSCs were treated
with sulforaphane and recombinant soluble TRAIL. We examined the effects of these drugs on NF-κB activity, self-
renewal and differentiation potential, and stemcell signaling via spheroid- and colony-forming assays, FACS and
western blot analyses, immunohistochemistry, and an antibody protein array in vitro and after
xenotransplantation. We largely found a stronger effect of sulforaphane on CSC properties compared to TRAIL,
though the agents acted synergistically when applied in combination. This was associated with the inhibition of
TRAIL-induced NF-κB binding; CXCR4, Jagged1, Notch 1, SOX 2, and Nanog expression; ALDH1 activity inhibition;
and the elimination of differentiation and self-renewal potential. In vivo, tumor engraftment and tumor growth
were strongly inhibited, without the induction of liver necrosis or other obvious side effects. These findings
suggest that sulforaphane shifts the balance from TRAIL-induced survival signals to apoptosis and thus explains
the observed synergistic effect. A nutritional strategy for high sulforaphane intake may target thecancer-specific
activity of TRAIL in CSCs.

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