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Cancer prevention and treatment
1. Cancer Prevention and
treatment
By targeting cellular transformation
Prepared by:
Low Zhao Xuan 0320156
Liew Kah Mun 0327195
Gloria Ng Hui Ying 0326869
Yeu Tze Hua 0327139
2. introduction
According to Health Ministry’s statistics(2014), it shows that cancer is the fourth highest cause of death
in government hospitals (13.02%).(Chow and Reporters, 2017)
Recently, the use of nutraceuticals in prevention of cancer is prevalence. Nutraceuticals is any
substance that may be considered a food or part of a food and provides medical or health benefits,
including the prevention and treatment of disease. Examples: polyphenols, selenium, Vitamin
D.(Fimdefelice.org, 2017)
There are different types of cancer treatment. Examples: surgery, chemotherapy and targeted
therapy.(Sudhakar, 2009)
In this assignment, we will be focusing on vitamin D as cancer prevention and targeted therapy as
cancer treatment.
3. Basic Principles on how cancerous cells develop
Alteration of genes that control cell division, apoptosis and cell adhesion causes transformation.
Cell division: Gene mutation accelerates cell division rates/inhibit normal controls on cell
division such as cell cycle arrest (Nature.com, 2017)
Apoptosis: Cancer cells unable to undergo programmed cell death exhibits longer lifespan
than normal cell, contributes to tumor formation. (Cooper, 2017)
Cell Adhesion: Loss of contact inhibition promotes cancerous cell metastasis
4. Application of vitamin D in cancer prevention
Calcitriol regulates cell cycle to prevent cancer formation (anti-proliferative)
- regulates gatekeeper’ gene such as p21and p27 that govern cell cycle.
- If a cell is damaged, the gatekeeper genes will be expressed,
causes production of regulators that inhibit the cyclin dependent kinase(CDK)
and prevent formation of cyclin CDK complex.
- This halts the cell cycle and allow cell repairs or elimination by apoptosis.
- Hence, vitamin D can control mutation and cancer cell productions. (Díaz et al., 2015)
Figure: cell cycle
regulation
(Cell Cycle
Regulation, no
date)
5. Application of vitamin D in cancer prevention
Calcitriol regulates apoptosis to prevent cancer formation
- suppresses the anti-apoptotic proteins BcI-2 and BcI-XL
- stimulates pro-apoptotic proteins Bax, Bak and Bad in various cancer cells.
Resulting in activation of caspases and committed to apoptosis.
- increase calcium concentration, releasing cytochrome c, glutathione
reduction results in increase in ROS and causes apoptosis
(Ingraham, Bragdon and Nohe, 2008)
Calcitriol regulates cell adhesion molecule to prevent cancer formation, pro
differentiating effect.
- stimulates production of E-cadherin, a transmembrane protein that help cells maintain
adherent phenotype.
- inhibits the function of beta catenin, a protein that regulate gene, causes cells to multiply.
(Díaz et al., 2015)
Figure shows the
proteins involved in
apoptosis (Cell Death,
no date)
6. Current Development and challenges
Current Development:
- Research of vitamin D to explore its therapeutic potential in oncology field.
- Establish adequate dietary cholecalciferol intervention strategy
Challenges:
- Exposure to sunlight is minimal nowadays, leading to decrease in
concentration of vitamin D in individuals.
- May be due to:
- establishment of UV radiation from sunlight increases skin cancer risk
How to overcome?
- Increase intake of vitamin D in the range of 1000-4000 IU
7. treatment
Targeted therapy
Use of certain drugs that target on specific genes or proteins related to cancer growth.
(Eg. Lenalidomide)
Lenalidomide - Lenalidomide is a 4-amino-glutamyl analogue of thalidomide with activity against various hematological and
malignancies by blocking the process that helps cancer cells to mutiply and spread. (Kotla et al., 2009)
Direct Anti Tumor Activity
Lenalidomide has shown anti proliferation activity against tumor cell by arrest cell cycle in G0-G1
phase. Lenalidomide upregulated the Cyclin dependant kinase (CDK) inhibitor, p21 waf-1, which used
to regulate the activity of CDKs. In contrast, the normal B cells from healthy donors were immune from
anti proliferation activity and did not show any upregulation of p21 expression. (Kotla et al., 2009)
8. Treatment - Lenalidomide
Anti-angiogenesis
Lenalidomide decrease expression of angiogenic factors:
● vascular endothelial growth factor (VEGF)
● Interleukin-6 (IL-6) (Kotla et al., 2009)
Lenalidomide specifically recognizes and binds to VEGF.
When VEGF is attached to Lenalidomide, it is unable to
activate its receptors. Without stimulation of VEGF,
bone marrow stromal cells and microvascular endothelial cells
cannot produce IL-6 which stimulate growth of new cells.
Thereby reducing angiogenesis, and thus blood supply rich in
nutrients and oxygen to cancerous cells are cut off.
Lenalidomide does not necessarily kill tumors; they instead may prevent tumors from growing.(National
Cancer Institute, 2017)
Figure shows the prevention of
angiogenesis.(Zetter, 2008)
9. Treatment- Lenalidomide
T cell Activation
B7 molecule on APC
+
CD28 on the T cell surface
Blockade of this interaction by CTLA-4-Ig
(B7 blocking antibody) is partially overcome by
Lenalidomide. Lenalidomide act on T cells via
B7-CD28 costimulatory pathway. Lenalidomide directly
induce tyrosine phosphorylation of CD28 on T cells
leading to activation of downstream targets
(examples: GRB-2-OS, NF-κb). T cell co-stimulation by
lenalidomide leads to an increased Th1 type cytokine
response resulting in increased secretion of IFN-γ
and IL-2 that in turn stimulate clonal T cell proliferation.(Kotla et al., 2009)
costimulatory
signal
(Augments T
cell response)
Figure shows action of Lenalidomide in T cell activation.(Kotla et al.,
2009)
10. Current development and challenges
Current development
Targeted drugs are still significantly improving to reduce the side effects and enhance the efficacy.
Challenges
Targeted drugs: -Side effects (eg. dry mouth, diarrhea, vomit and etc.) (Kotla et al., 2009)
-Might not work on some patient or stop working after sometime
-Ethical issues on drug improvement and development
11. conclusion
Cancer cell is formed due to the alteration of gene controlling cell division,
apoptosis and cell adhesion.
Vitamin D as a prevention nutraceutical have anti-proliferative effect and pro
differentiating effects that prevent normal cells from transforming into cancer
cells.
Calcitriol also regulates apoptosis cascade to prevent formation of cancer cells.
Targeted therapy is type of a treatment that can target on specific gene or
protein. Lenalidomide is a type of drug that has direct anti-tumor activity, anti
angiogenesis activity and T-cell activation.
12. References
Cancer Awareness. (2017). Cancer Awareness. [online] Available at: http://ontariocancerawareness.weebly.com/ [Accessed
13 Sep. 2017].
Cell Cycle Regulators | Cell Cycle Regulation (no date). Available at: https://biogirls4life.wordpress.com/cell-cycle-
regulators/ (Accessed: 14 September 2017).
Cell Death (no date). Available at: http://classes.kumc.edu/som/CellBiology/processes/celldeath/tut3.html (Accessed: 14
September 2017).
Chow, M. and Reporters, F. (2017). 1 in 4 M'sians will get cancer by 75 years old. [online] Free Malaysia Today. Available
at: http://www.freemalaysiatoday.com/category/nation/2016/04/04/1-in-4-msians-will-get-cancer-by-75-years-old/ [Accessed
14 Sep. 2017].
Cooper, G. , 2017, The Development and Causes of Cancer. <https://www.ncbi.nlm.nih.gov/books/NBK9963/ >viewed on
13 Sep. 2017
Díaz, L. et al. (2015) ‘Mechanistic Effects of Calcitriol in Cancer Biology.’, Nutrients. Multidisciplinary Digital Publishing
Institute (MDPI), 7(6), pp. 5020–50. doi: 10.3390/nu7065020.
13. Reference
Fimdefelice.org. (2017). WHAT IS A TRUE NUTRACEUTICAL?. [online] Available at: http://www.fimdefelice.org/p2462.html
[Accessed 14 Sep. 2017].
Ingraham, B. A., Bragdon, B. and Nohe, A. (2008) ‘Molecular basis of the potential of vitamin D to prevent cancer’, Current
Medical Research and Opinion, 24(1), pp. 139–149. doi: 10.1185/030079908X253519.
Kotla, V., Goel, S., Nischal, S., Heuck, C., Vivek, K., Das, B. and Verma, A. (2009). Mechanism of action of lenalidomide in
hematological malignancies. Journal of Hematology & Oncology, 2(1), p.36.
National Cancer Institute. (2017). Angiogenesis Inhibitors. [online] Available at: https://www.cancer.gov/about-
cancer/treatment/types/immunotherapy/angiogenesis-inhibitors-fact-sheet [Accessed 14 Sep. 2017].
Nature.com., 2017, Cell Division, Cancer | Learn Science at Scitabe. <https://www.nature.com/scitable/topicpage/cell-
division-and-cancer-14046590> viewed on 13 Sep. 2017
Sudhakar, A. (2009). History of Cancer, Ancient and Modern Treatment Methods. Journal of Cancer Science & Therapy,
01(02), p.i-iv.
14. Reference
Uribesalgo I, e., 2017, From oncogene to tumor suppressor: the dual role of Myc in leukemia.
<https://www.ncbi.nlm.nih.gov/pubmed/22510570 > viewed on 9 Sep. 2017
Zetter, B. (2008). The scientific contributions of M. Judah Folkman to cancer research. Nature Reviews Cancer, 8(8),
pp.647-654.
27.109.7.67. (2017). ::E-Content NMEICT ::. [online] Available at: http://27.109.7.67:1111/econtent/vitamins/deficiency-and-
factors.php [Accessed 13 Sep. 2017].
Editor's Notes
To this date, vitamin D research seeks to understand the mechanisms through which calcitriol acts and to explore its therapeutic potential in the oncology field. Even though vitamin D stands as a promising safe alternative for cancer prevention and progression to a reasonable extent, an adequate dietary cholecalciferol intervention strategy still waits to be correctly established.
The drugs can: i) Block or turn off signals that tell cancer cells to grow and divide
ii) Prevent cancerous cells from living longer than normal
iii) Kill the cancer cells
bone marrow stromal cells: multipotent stem cells that can differentiate into a variety of cell types.
Immunomodulation: modulation (regulatory adjustment) of the immune system
B7: peripheral membrane protein on APC, when paired with either a CD28 or CD152 (CTLA-4) surface protein on a T cell, can produce a costimulatory signal or a coinhibitory signal to enhance or decrease the activity of a MHC-TCR signal between the APC and the T cell, respectively
CD28: one of the proteins expressed on T cells that provide co-stimulatory signals required for T cell activation and survival
CTLA4 (cytotoxic T-lymphocyte-associated protein 4): protein receptor that, functioning as an immune checkpoint, downregulates immune responses
Th1 cells activate antigen-presenting cells (APC) and induce limited production of the type of antibodies that can enhance the uptake of infected cells or tumor cells into APC.
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication.
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines
Interferon (IFN)-γ is the uppermost cytokine implicated in anti-tumor immunity. ( cytostatic, pro-apoptotic and immune-provoking effects)
Side effect : dry mouth, diarrhea, vomit, dizzyness. this drug can be absorbed through the skin and lungs and may harm an unborn baby causing birth defect, women who are pregnant or who may become pregnant should not handle this medication or breathe the dust from broken capsules.