ROLE OF APOPTOSIS IN CANCER PATHOPHYSIOLOGY_ (Ananya Chanda).pdf

1. Role of Apoptosis
in Cancer
Pathophysiology
Prepared by:
Ananya Chanda
Roll No. : 10020220001
Registration No. : 203002320210002
Subject Code: MPT-2986
Department of Pharmaceutical Sciences &
Technology
M.Pharm , 1st Year 2nd Semester (Pharmacology)
Maulana Abul Kalam Azad University of Technology
(In-house), West Bengal

2. Contents
• Apoptosis
• Why Apoptosis is important?
• Mechanisms of Apoptosis
• Role of apoptosis in cancer development
• Treatment of cancer
• Conclusion
• References

3. APOPTOSIS
• Genetical Programmed cell death.
• Derived from the Greek words “aπο“ and
“πτωsιζ“ meaning “dropping off” and refers to the
falling of leaves from trees in autumn.
• Cell death occurs during normal physiological
condition and forced apoptosis (viral infections,
protein misfolding, DNA damage) can take place
during irreparable cell damage.
• Essential for development and survival of living
organisms.
Source: Kumar V, Abbas AK, Aster JC. Robbins And Cotran Pathologic
Basis of Disease. 9th ed. Philadelphia: Elsevier Saunders; 2015. 41-52 p.
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4. WHY APOPTOSIS IS IMPORTANT?
• Elimination of cells that are no longer required.
• Maintain normal number of cells in tissue.
Tissue
Homeostasis
• Destruction of cells during Embryogenesis
• Seperation of webbed fingers and toes
Development
and
differentiation
• Elimination of virus infected cells by
cytotoxic T lymphocyte.
• In HIV infections, hepatitis, adenovirus.
Immune
system
• If irreparable cell damage then cell triggers
intrinsic mechanism to induce apoptosis to
avoid mutation or malignant formation of
the damaged cell.
Cell damage Source: Morphogenesis by apoptosis. Genetically
programmed apoptosis (individual cell death) causing
separation of the fingers during
embryogenesis.[Internet].2015.Avalable from:
https://clinicalgate.com/of-growth-differentiation-and-
morphogenesis/
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5. MECHANISMS OF APOPTOSIS
Source: Biomed research international. The Role of Intrinsic Pathway in Apoptosis Activation and Progression in Peyronie’s
Disease.[Internet].2014.Available from: https://www.hindawi.com/journals/bmri/2014/616149/
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6. ROLE OF APOPTOSIS IN CANCER DEVELOPMENT
• Cancer occurs due to genetic changes and inhibition of cell death which leads to the
transformation of a normal cell into a malignant cell.
• In 1970’s, Kerr et al had linked apoptosis to the elimination of malignant cells,
hyperplasia and tumour progression.
• Reduction of apoptosis or its resistance mechanism plays a vital role in carcinogenesis.
The mechanisms by which evasion of apoptosis occurs can be broadly dividend into:
• 1) Disrupted balance of pro-apoptotic and anti-apoptotic proteins
• 2) Apoptosome defects
• 3) Reduced caspase function
• 4) Impaired death receptor signaling
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7. CONT…
1) DISRUPTED BALANCE OF PRO-APOPTOTIC AND ANTI-
APOPTOTIC PROTEINS
• BCL-2 Family proteins alteration
➢ An overexpression of anti-apoptotic proteins or an underexpression
of pro-apoptotic proteins or a combination of both led to the
dysregulated apoptosis.
Examples
➢ Overexpression of Bcl-2, Bcl-xL protected prostate cancer cells from
apoptosis and multi-drug resistance phenotype in tumour cells and
prevent them from undergoing apoptosis .
➢ Bax and Bak mutations causes impaired apoptosis have been
reported in colon and gastric carcinomas.
➢ Underexpression of Bid protein can develop chronic myelomonocytic
leukemia.
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8. CONT..
• Defects/ Mutations in p53
➢ Tumour protein 53 (or TP 53), is one of the best
known tumour suppressor proteins encoded by
the tumour suppressor gene TP53 located at the
short arm of chromosome 17.
➢ Known as “guardian of genome”
➢ Oncogenic property develops- defects or mutation
of p53.
➢ 50% of human cancers
Examples
➢ Osteosarcoma and myosarcoma
➢ Breast cancer
➢ Liver cancer
➢ Lung cancer
➢ Colorectal cancer
Source: Cancer and the Cell Cycle. Tumor Suppressor Gene.[Internet].Available from:
https://courses.lumenlearning.com/boundless-biology/chapter/cancer-and-the-cell-cycle/
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9. CONT..
2) APOPTOSOME DEFECTS
• Defective Cyt-C dependent caspase 9 activation in the presence of normal or elevated
Apaf1 levels can develop some cancers.
• Inactivation of Apaf1 induces p53 defects.
Examples
➢ Melanomas, leukemias, glioblastomas, and cervical carcinomas.
➢ Sequestration of Apaf1 into lipid rafts has also been demonstrated in Burkitt lymphoma
cells providing another molecular mechanism for apoptosome dysfunction.
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10. CONT..
3) REDUCED CASPASE FUNCTION
• Caspases (Cysteine-dependent aspartate specific proteases) are proteases that contain a
cysteine in their active center and are able to cleave proteins.
• Initiator caspases are 2, 8, 9 and 10
• Effector caspases are 3,6 and 7
• Impairment in caspase function or low level may lead to a decreased in apoptosis and
carcinogenesis.
Examples
➢ Downregulation of caspase-9 can cause stage II colorectal cancer.
➢ Loss of caspases-3 expression and function could contribute to breast cancer cell
survival.
➢ Codownregulation of both caspase-8 and -10 may contribute to the pathogenesis of 08

11. CONT..
4) IMPAIRED DEATH RECEPTOR SIGNALING
• Type 1 TNF receptor (TNFR1) and a related protein called Fas
(CD95) and their ligands are called TNF and Fas ligand
(FasL).Other examples of death receptors include DR3 or APO-3,
DR4 or (TRAIL-1) or APO-2, DR5 or TRAIL-2, DR 6, EDAR and
NGFR.
• Downregulation or impairment of receptors function and reduced
level in the death signals, contribute to impaired signaling and
reduction of apoptosis.
Examples
➢ Cervical carcinogenesis- Loss of Fas and the dysregulation of FasL,
DR4, DR5, and tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL).
➢ Over-expression of FAS-L- hepatocarcinomas, esophageal cancers,
breast cancers, melanomas, astrocytomas , metastatic colon
cancers, gastric cancers. 09

12. CANCER TREATMENT
TREATMENT STRATEGY ANTI-CANCER AGENTS
1. Targeting the Bcl-2 family of proteins
• Oblimersen sodium (first agent targeting Bcl-2 to enter
clinical trial)
• Sodium butyrate, Depsipetide, Fenretinide &
Flavipirodol (affects gene expression)
• Gossypol, ABT-737, ABT-263, GX15-070 & HA14-1
(affects proteins itself)
• ABT-737 (inhibits anti-apoptotic proteins)
2. p53-based gene& drug therapy
• Genetically engineered oncolytic adenovirus, ONYX-015, in
which the E1B-55 kDa gene has been deleted.
• Phikan083 (restores mutant p53)
3. Caspase-based drug & gene therapy
• Apoptin reported to selectively induce apoptosis in
malignant but not normal cells
• Human caspase-3 gene therapy used in addition to
etoposide treatment in an liver tumour model reported to
induce extensive apoptosis and reduce tumour volume
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13. CONCLUSION
• Dysregulation of apoptotic pathways play a vital role in cancer development. So, the
treatment strategies should be such that the side effects of tumor resistance should less,
the molecules targeting apoptosis should only act on single pathway or protein and the
most challenging task is to find out the treatment that can selectively induce apoptosis
in malignant cells and not the normal ones while maintaining homeostasis.
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14. REFERENCES
1. Kumar V, Abbas AK, Aster JC. Robbins And Cotran Pathologic Basis of Disease. 9th ed.
Philadelphia: Elsevier Saunders; 2015. 41-52 p.
2. Wong RS. Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res
[Internet].2011;30(1):87. Available from:
https://jeccr.biomedcentral.com/articles/10.1186/1756-9966-30-87#citeas/ accessed on
09.06.2021
3. Favaloro B, Allocati N, Graziano V, Di Ilio C, De Laurenzi V. Role of apoptosis in disease.
Aging Albany NY [Internet].2012;4(5):330-49. Available from:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384434/ accessed on 10.06.2021
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15. THANK YOU