6. Table of content
Purpose
Description
Treatment option of cancer
Classification
Mechanism of anticancer drugs
Pre–clinical Evaluation
Some Modern treatment of cancer
7. Table of content
Anticancer effects and molecular mechanisms of
epigallocatechin-3-gallate
Melatonin anticancer effects
Anticancer effect of calycopterin via PI3K/ Akt and MAPK
signaling pathways, ROS-mediated pathway and mitochondrial
dysfunction in hepatoblastoma cancer (HepG2) cells.
Anticancer effects of garlic and garlic-derived compounds
for breast cancer control
Anticancer Effect of Ginger Extract against Pancreatic Cancer
Cells Mainly through Reactive Oxygen Species-Mediated Autotic
Cell Death.
Side effect of anticancer drug
8. Purpose
Anticancer drugs are used to control the growth of cancerous ce
lls. Cancer is commonly defined as the uncontrolledgrowth of ce
lls, with loss of differentiation and commonly, with metastasis, s
pread of the cancer to other tissues andorgans. Cancers are mali
gnant growths. In contrast, benign growths remain encapsulated
and grow within a well- definedarea.
Although benign tumors may be fatal if untreated, due to pressu
re on essential organs, as in the case of a benign brain
tumor, surgery or radiation are the preferred methods of treatin
g growths which have a well defined location. Drug
therapy is used when the tumor has spread, or may spread, to all
areas of the body.
9. Description
Several classes of drugs may be used in cancer treatment, depen
ding on the nature of the organ involved. For example,
breast cancers are commonly stimulated by estrogens, and may
be treated with drugs that inactivate the sex hormones.
Similarly, prostate
cancer may be treated with drugs that inactivate androgens, the
male sex hormone. However, themajority of antineoplastic drugs
act by interfering with cell growth. Since cancerous cells grow
more rapidly than othercells, the drugs target those cells that are
in the process of reproducing themselves. As a result, antineopla
stic drugs willcommonly affect not only the cancerous cells, but
others cells that commonly reproduce quickly, including hair fol
licles, ovaries and testes, and the blood-forming organs.
10. Treatment options of cancer:
No Treatment: Before 1940
Surgery: before 1955
Radiotherapy: 1955~1965
Chemotherapy: after 1965
Immunotherapy and Gene therapy
11. Classification
According to chemical structure and sources of drugs
Alkylating Agents, Antimetabolite, Antibiotics, Plant Extracts, Hormones
and Others
According to biochemistry mechanisms of anticancer action:
Block nucleic acid biosynthesis
Direct influence the structure and function of DNA
Interfere transcription and block RNA synthesis
Interfere protein synthesis and function
Influence hormone homeostasis
According to the cycle or phase specificity of the drug:
Cell cycle nonspecific agents (CCNSA) & Cell cycle specific agents (CCSA)
12. Mechanism of Anticancer Drugs
Block nucleic acid (DNA, RNA) biosynthesis
Directly destroy DNA and inhibit DNA reproduction
Interfere transcription and block RNA synthesis
Interfere protein synthesis and function
Influence hormone homeostasis
14. In vitro cytotoxicity studies:
1990 : NCI-60 screen
Cytotoxicity assays on panel of human cancer cell lines
MTT-assay
SRB- assay
3H-thymidine uptake assay
Fluorescence Dye exclusion tests
Clonogenic assays
Cell counting assay
15. In vitro cytotoxicity studies:
Advantages
Reduce the usage of animals.
Less time consuming,
Cost effective &
Easy to manage
Able to process a larger number of
compounds quickly with minimum
quantity.
Range of concentrations used are
comparable to that expected for in
vivo studies
Disadvantages:
Difficulty in maintaining of
cultures.
Show negative results for the
compounds which gets activated
after body metabolism and vice
versa.
Impossible to ascertain the
Pharmacokinetics .
17. Preclinical Toxicity Studies
Aimed at predicting
(a) Safe starting dose & dosage regimen for human clinical trials(P1)
(b) The toxicities of the compound, &
(c) The likely severity and reversibility of drug toxicities.
Regulatory requirement : Two acute preclinical toxicity studies
1. Rodent (mice) - single- and multiple-dose lethality studies.
2. Non rodent (dogs) - single- and multiple-dose confirmatory toxicity.
Cytotoxic & non cyotoxic drugs
18. Acute Toaxicity Studies
First mouse given a single injection (IP, IV, SC, IM or PO) of 400 mg/kg (or
lower if the compound is extremely potent)
Second mouse - 200 mg/kg &
Third mouse - 100 mg/kg
The mice are observed for a period of 2 weeks & sacrificed if there are signs
of significant toxicity
If all 3 mice must be sacrificed, the next 3 dose levels (50, 35 and 12.5
mg/kg) are tested in a similar manner
This process is repeated until a tolerated dose is found designated as MTD.
19. In Vivo Hollow Fibre Assay
In vivo screening tool implemented in 1995 by NCI
12 human tumor cell lines (lung, breast, colon, melanoma,
ovary, and glioma
Cells suspended into hollow polyvinylidene fluoride fibers
implanted IP or SC in lab mice
After in vivo drug treatment, fibers are removed and analyzed in
vitro
Antitumor (growth inhibitory) activity assessed
21. Why mice?
Mice are small, easy to handle.
Short generation time & accelerated lifespan,manageable costs,
space, and time.
Striking similarity to humans in anatomy, physiology, and
genetics.
Over 95% of the mouse genome is similar to humans.
Many of the genes responsible for complex diseases are shared
between mice and humans.
Mouse genome can be directly manipulated.
24. Anticancer effects and molecular mechanisms of
epigallocatechin-3-gallate
Abstract
Epigallocatechin-3-gallate (EGCG) is a type of catechin found in green tea.
EGCG exhibits a variety of activities, including anti-inflammatory,
antidiabetes, antiobesity, and antitumor. In this review, I focus on the
antitumor effects of EGCG.
EGCG inhibits carcinogen activity, tumorigenesis, proliferation, and
angiogenesis, and induces cell death. These effects are associated with
modulation of reactive oxygen species (ROS) production. Although EGCG has
a dual function of antioxidant and pro-oxidant potential, EGCG-mediated
modulation of ROS production is reported to be responsible for its anticancer
effects.
25. The EGCG-mediated inhibition of nuclear factor-κb signaling is
also associated with inhibition of migration, angiogenesis, and
cell viability. Activation of mitogen-activated protein kinases
activity upregulates the anticancer effect of EGCG on migration,
invasion, and apoptosis.
In addition, EGCG could also induce epigenetic modification by
inhibition of DNA methyltransferase activity and regulation of
acetylation on histone, leading to an upregulation of apoptosis.
Although EGCG promotes strong anticancer effects by multiple
mechanisms, further studies are needed to define the use of
EGCG in clinical treatment.
26. Introduction
Green tea is one of most consumed beverages around the
world. It is extracted from the leaves of Camellia sinensis. Green
tea is composed of proteins (15–20% dry weight), amino acids
(1–4% dry weight), fiber (26% dry weight), carbohydrates (5–
7% dry weight), minerals and trace elements (5% dry weight),
lipids (5% dry weight), and polyphenols (30% dry weight).
Among polyphenols, green tea is characterized by the presence
of large amounts of catechins, including epigallocatechin-3-
gallate (EGCG), epigallocatechin (EGC), epicatechin-3-gallate,
and epicatechin (EC).
27. Among them, EGCG has been known as the most powerful
protective agent in cancer chemoprevention.The beneficial
effects of EGCG are reported in the treatment of cancer,
cardiovascular diseases, diabetes,neurodegenerative
diseases, and liver diseases. This review describes the
chemopreventive effect and molecular mechanisms of EGCG.
28. Structure of EGCG
EGCG has three aromatic rings (A, B, and D) that are linked together by a pyran
ring . The health-promoting function of EGCG is attributed to its structure. For
example, the antioxidant activity of EGCG results from the transfer of hydrogen
atom or single-electron transfer reactions, involving hydroxyl groups of the B
and/or D rings. Furthermore, the B and D rings are associated with an inhibition of
proteasome activity in vitro. The A ring of EGCG is involved in the inhibition of
heat-shock protein 90.The hydroxyl group at the 5′ position in the B ring also
inhibits the growth of Helicobacter pylori in the stomach
29. Bioavailability of EGCG
A preclinical pharmacokinetic study reported that EGCG has low
oral bioavailability (2–13%) in rodents. Multiple processes
contribute to the low bioavailability of EGCG, including the
following:
(1) low solubility in the gastrointestinal fluid;
(2) slow and hard absorption;
(3) fast metabolism and elimination system;
(4) wide tissue distribution.
30. Anticancer effects of EGCG
1) Inhibition of carcinogen activity and tumorigenesis
2) Inhibition of tumor proliferation and angiogenesis
3) Inhibition of tumor migration and invasion
4) Induction of cell death
4-1) Caspase-dependent apoptosis
4-2) Caspase-independent apoptosis
4-3) Lysosomal membrane permeabilization-mediated cell
death
4-4) Autophagy
32. 1-ROS
ROSs are critical signaling molecules that modulate anticancer
effects. First, EGCG could directly scavenge ROS. The antioxidant
activity of EGCG results from the transfer of hydrogen atom or
single-electron transfer reactions, involving hydroxyl groups of
the B and/or D rings. Electron paramagnetic resonance (EPR)
spectroscopy and density functional theory calculations have
been used to examine the redox properties of the green tea
polyphenols, such as EGCG. Using EPR, it is reported that EGCG
reacts with O2–, which induces oxidation of the D
ring. Furthermore, EGCG also could efficiently scavenge OH and
O2–.The antioxidant effect of EGCG is related to anticancer
function.
33. 2- Nuclear factor-κB
Nuclear factor-κB (NF-κB) has been known as a regulator of
gene expression, which plays a critical role in the development
and progression of various stages of cancer, such as
proliferation, migration, invasion, and apoptosis. In normal cells,
the dimer of NF-κB is sustained in cytosol due to its interaction
with the inhibitors of NF-κB (IκB). When cells are stimulated by
NF-κB activators, such as growth factor and proinflammatory
cytokines, IκB kinase (IKK) phosphorylates IκB, following which
IκB undergoes proteasome-dependent degradation.
34. 3- MAPKs
MAPKs are composed of extracellular signal-regulated
kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase
(JNK), and the deregulation of MAPK cascades
contributes to cancer. Suppression of ERK
phosphorylation by EGCG decreases MMP-2 and
MMP-9 activity by the downregulation of MMP-2 and
MMP-9 messenger RNA (mRNA) in fibrosarcoma
cells,95 and inhibition of ERK and JNK by EGCG reduces
MMP-9 mRNA expression in phorbol 12-myristate
13-acetate-treated gastric carcinoma cells
35. 4. Epigenetic modification
Cancer is modulated by both genetic and epigenetic events.
Epigenetic events could alter gene expression without changing
the primary DNA sequence, and epigenetic mechanisms include
DNA methylation and histone acetylation. These epigenetic
changes are involved in the alteration of gene function and
expression, leading to malignant cellular formation. Among
various epigenetic modifications, DNA methylation is most
extensively studied in mammals. Hypermethylation on the DNA
molecule limits the binding of transcription factors to promoters,
resulting in the recruitment of additional silencing-associated
proteins and gene silencing. This methylation is mediated by
DNA methyltransferase (DNMT). EGCG has been known as an
inhibitor of DNMT by direct inhibitory interaction with the
catalytic site of DNMT
36. Safety of EGCG
Although tea polyphenols are safe and high consumption of tea polyphenols
(600–1800 mg/day) has no adverse reaction, toxicity of EGCG has also been
reported. Schmidt et al105 reported that EGCG is a major contributor to the
cytotoxic effect of green tea extracts in hepatocytes. Furthermore, treatment
with EGCG enhanced high glucose-mediated beta-cell damage in diabetic
rats.106 EGCG increases the reduction of islet cell mass and number of
insulin-positive beta cells through the production of ROS at nanomolar
plasma concentrations.106 In addition, there are many studies about the toxic
effects of EGCG in inducing hepatic failure.
37. Conclusion
EGCG promotes anticancer effects by modulation of
multiple processes, including inhibition of carcinogen
activity, tumorigenesis, proliferation, and angiogenesis,
and induction of cell death. These effects are associated
with modulation of ROS production, inhibition of NF-κ
B, down/ upregulation of MAPKs activation, and
regulation of epigenetic change. Although EGCG
exhibits a strong anticancer effect in vitro, further
studies are needed to define the use of EGCG in clinical
treatment.
40. Abstract
Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main
hormone produced by the pineal gland, not only regulates
circadian rhythm, but also has antioxidant, anti-ageing and
immunomodulatory properties. MLT plays an important role
in blood composition, medullary dynamics, platelet genesis,
vessel endothelia, and in platelet aggregation, leukocyte
formula regulation and hemoglobin synthesis. Its significant
atoxic, apoptotic, oncostatic, angiogenetic, differentiating and
antiproliferative properties against all solid and liquid tumors
have also been documented.
41. MLT can exert both direct and indirect anticancer effects in
factorial synergy with other differentiating, antiproliferative,
immunomodulating and trophic molecules that form part of the
anticancer treatment formulated by Luigi Di Bella (Di Bella
Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin
D3, prolactin inhibitors, chondroitin-sulfate). The interaction
between MLT and the DBM molecules counters the multiple
processes that characterize the neoplastic phenotype (induction,
promotion, progression and/or dissemination, tumoral
mutation). All these particular characteristics suggest the use of
MLT in oncological diseases.
42.
43. The Main Direct Anticancer Mechanisms of
Melatonin
1. Pro-Apoptotic
2. Antiproliferative
3. Differentiating
4. Anti-Angiogenetic
44. The Main Indirect Anticancer Mechanisms of
Melatonin
1. Free Radical Scavenger Action
2. Myeloprotective/ Myelostimulant Action
3. Melatonin’s Action in Regulating the Immune
System
45. Insoluble in water (A), melatonin (MLT) dissolves in ethyl alcohol. Since
absorption and bio-availability are linked with solubility, in the Luigi Di Bella
formulation it is combined with a hydrogen bond to adenosine (B), thus
becoming perfectly soluble and absorbable, with its biological-functional
activities being reinforced.
46. Mechanisms of Action and Physiology of
Melatonin in Tumors
1. The Receptorial System
2. Other Mechanisms
.3. The Amine Precursor Uptake and Decarboxylation System
(APUD)
.4. Platelets and the APUD System
5. Melatonin’s Action on Microtubules
47.
48. Anticancer action of melatonin: main molecular mechanisms.
(1) Direct anti-oxidant enzyme activation; (2): bind with ML3
receptor; (3) direct antioxidant activity (scavenger); (4) gene
expression regulation (differentiation); (5) calmodulin
degradation: antiproliferative; (6) AC inhibition:
antiproliferative. ML1/2: melatonin type receptor 1-2; SOD:
super oxide dismutase; GRS: glutatione reductase; CAT: catalase;
ML3/QR3: melatonin type receptor 3/ quinone reductase 2; AC:
adenylate ciclase; ROS: reactive oxygen species; RNS: reactive
natrium species; AFMK: N(1)-acetyl-N(2)-formyl-5-
methoxykynuramine.
49. Anticancer effect of calycopterin via PI3K/Akt and MAPK signaling
pathways, ROS-mediated pathway and mitochondrial dysfunction
in hepatoblastoma cancer (HepG2) cells.
50. Abstract
Calycopterin is a flavonoid compound isolated from
Dracocephalum kotschyi that has multiple medical uses, as an
antispasmodic, analgesic, anti- hyperlipidemic, and
immunomodulatory agents. However, its biological activity and
the mechanism of action are poorly investigated. Herein, they
investigated the apoptotic effect of calycopterin against the
human hepatoblastoma cancer cell (HepG2) line. They
discovered that calycopterin-treated HepG2 cells were killed off
by apoptosis in a dose-dependent manner within 24 h, and was
characterized by the appearance of nuclear shrinkage, cleavage
of poly (ADP-ribose) polymerase and DNA fragmentation.
51. Calycopterin treatment also affected HepG2 cell viability: (a) by inhibiting
cell cycle progression at the G2/M transition leading to growth arrest and
apoptosis; (b) by decreasing the expression of mitotic kinase cdc2, mitotic
phosphatase cdc25c, mitotic cyclin B1, and apoptotic factors pro-caspases-3
and -9; and (c) increasing the levels of mitochondrial apoptotic-related
proteins, intracellular levels of reactive oxygen species, and nitric oxide.
They further examined the phosphorylation of extracellular signal-related
kinase (ERK 1/2), c-Jun N-terminal kinase, and p-38 mitogen-activated
protein kinases (MAPKs) and found they all were significantly increased in
HepG2 cells treated with calycopterin. Interestingly, they discovered that
treated cells had significantly lower Akt phosphorylation. This mode of action
for calycopterin in their study provides strong support that inhibition of PI3K/
Akt and activation of MAPKs are pivotal in G2/M cell cycle arrest and
apoptosis of human hepatocarcinoma cells mediated by calycopterin.
52. Introduction
Apoptosis, or programmed cell death has been described as a
mechanism by which cells undergo a natural dying process to
control cell proliferation or in response to DNA damages. These
apoptotic and cell death program are used to develop novel
therapies against cancer cell using agents with cytotoxic
properties as chemotherapy and radiation therapy.
Two main core pathway that established in apoptosis are;
(a) The cell death receptor-mediated extrinsic pathway and the
mitochondrial-mediated intrinsic pathway
(b) The intrinsic pathway that leads to apoptosis under the
control of mitochondria and its associated molecules.
55. Anticancer effects of garlic and
garlic-derived compounds for
breast cancer control.
56. Abstract
Garlic and garlic-derived compounds reduce the development of mammary
cancer in animals and suppress the growth of human breast cancer cells in
culture.
Oil-soluble compounds derived from garlic, such as Di Allyl Di Sulfide (DADS), are
more effective than water-soluble compounds in suppressing breast cancer.
Mechanisms of action include the activation of metabolizing enzymes that detoxify
carcinogens, the suppression of DNA adduct formation, the inhibition of the
production of reactive oxygen species, the regulation of cell-cycle arrest and the
induction of apoptosis.
57. Selenium-enriched garlic or organoselenium compounds provide
more potent protection against mammary carcinogenesis in rats and
greater inhibition of breast cancer cells in culture than natural garlic
or the respective organosulfur analogues.
DADS synergizes the effect of eicosapentaenoic acid, a breast
cancer suppressor, and antagonizes the effect of linoleic acid, a
breast cancer enhancer. Moreover, garlic extract reduces the side
effects caused by anti-cancer agents. Thus, garlic and garlic-derived
compounds are promising candidates for breast cancer control.
58. Anticancer Effect of Ginger Extract against
Pancreatic Cancer Cells Mainly through Reactive
Oxygen Species-Mediated Autotic Cell Death.
59. Abstract
The extract of ginger (Zingiber officinale Roscoe) and its major pungent
components, [6]-shogaol and [6]-gingerol, have been shown to have an anti-
proliferative effect on several tumor cell lines. However, the anticancer
activity of the ginger extract in pancreatic cancer is poorly understood. Here,
I demonstrate that the ethanol-extracted materials of ginger suppressed cell
cycle progression and consequently induced the death of human pancreatic
cancer cell lines, including Panc-1 cells. The underlying mechanism entailed
autosis, a recently characterized form of cell death, but not apoptosis or
necroptosis. The extract markedly increased the LC3-II/LC3-I ratio, decreased
SQSTM1/p62 protein, and enhanced vacuolization of the cytoplasm in Panc-
1 cells. It activated AMPK, a positive regulator of autophagy, and inhibited
mTOR, a negative autophagic regulator.
60. The autophagy inhibitors 3-methyladenine and chloroquine partially
prevented cell death. Morphologically, however, focal membrane rupture,
nuclear shrinkage, focal swelling of the perinuclear space and electron dense
mitochondria, which are unique morphological features of autosis, were
observed. The extract enhanced reactive oxygen species (ROS) generation,
and the antioxidant N-acetylcystein attenuated cell death. Our study revealed
that daily intraperitoneal administration of the extract significantly
prolonged survival (P = 0.0069) in a peritoneal dissemination model and
suppressed tumor growth in an orthotopic model of pancreatic cancer (P <
0.01) without serious adverse effects. Although [6]-shogaol but not [6]-
gingerol showed similar effects, chromatographic analyses suggested the
presence of other constituent(s) as active substances. Together, these results
show that ginger extract has potent anticancer activity against pancreatic
cancer cells by inducing ROS-mediated autosis and warrants further
investigation in order to develop an efficacious candidate drug.
62. Chemotherapy can cure cancer because it kills cells. It kills cancer cells and it
can kill normal cells. Killing normal cells can cause some unpleasant side
effects. The side effects vary from one drug to another for many reasons. Not
all chemo drugs cause hair loss, for example.
Some of the more common side effects are:
Low blood counts causes an increased possibility of developing infection or
anemia
Tiredness
Mouth soreness
Nausea, vomiting
Loss of appetite
Constipation or diarrhea
Hair loss
Skin changes or reactions
Pain or nerve changes
Changes in fertility and sexuality
63. The good news about these side effects is that there are ways to ease
most of the symptoms. Sometimes, however, certain side effects can
have long lasting or permanent effects. For example, certain
chemotherapy drugs can result in infertility or the inability to
father a child which may be permanent. Certain options such as
sperm banking may be available. Please talk to your doctor or
nurse about any concerns before starting chemotherapy.