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Dr Satyabrata Sahoo
DM Clinical Pharmacology Resident
Dept of Clinical & Experimental Pharmacology, CSTM
Kolkata
10/29/2021 1
Introduction
 Apoptosis- Programmed cell death
 Orderly and efficient removal of damaged cells following DNA damage
or during development
 Very complex and involves many signaling pathways
 Triggered through caspase-mediated intrinsic and extrinsic pathways
 Balance between Pro apoptotic and anti apoptotic regulators important
key point in apoptosis.
 The dysregulation of apoptosis is a symptom in a wide variety of
diseases.
 Accelerated apoptosis is found in infertility, immunodeficiency, and
acute and chronic degenerative diseases
 Delayed or inhibited apoptosis is present in cancer and autoimmunity
10/29/2021 2
10/29/2021 3
10/29/2021 4
Int. J. Mol. Sci. 2018
10/29/2021 5
Int. J. Mol. Sci. 2018
10/29/2021 6
www.impactaging.com 607 AGING, April 2016, Vol. 8 No.4
10/29/2021 7
www.impactaging.com 607 AGING, April 2016, Vol. 8 No.4
10/29/2021 8
Int. J. Mol. Sci. 2018, 19, 448
10/29/2021 9
Apoptosis-based therapies U Fischer and K Schulze-Osthoff
10/29/2021 10
Apoptosis-based therapies U Fischer and K Schulze-Osthoff
10/29/2021 11
Apoptosis-based therapies U Fischer and K Schulze-Osthoff
10/29/2021 12
Apoptosis-based therapies U Fischer and K Schulze-Osthoff
10/29/2021 13
Apoptosis-based therapies U Fischer and K Schulze-Osthoff
10/29/2021 14
Apoptosis-based therapies U Fischer and K Schulze-Osthoff
10/29/2021 15
Apoptosis-based therapies U Fischer and K Schulze-Osthoff
10/29/2021 16
Apoptosis-based therapies U Fischer and K Schulze-Osthoff
Novel Therapeutic agents Targeting Apoptosis
 Oblimersen sodium-AML
 Troglitazone-Advanced prostate cancer
 Fenretinide- Rhabdomyosarcoma, ovarian carcinoma
 Flavopiridol-AML,SCLC
 Gossypol-SCLC,NSCLC
 R7112-Advanced solid tumors
 APR-246- malignancies, hormone refractory prostate cancer
 Dulanermin-Non Hodgkins lymphoma
 Tigatuzumab- Breast cancer
 Decitabine-Caspase 8 promoters booster
10/29/2021 17
Summary
 Apoptosis is a cellular procedure regulated by diverse groups
of regulatory molecules in which activation of caspase plays a
crucial role.
 Depending on the molecular target, different strategies are
being employed.
 Fundamental features of human cancers is evasion of
apoptosis.
 Leading to tumor progression and resistance to cancer
treatment.
10/29/2021 18
Cont..
 Biologicals including death ligands or agonistic and
antagonistic antibodies that inhibit or trigger death receptor
signaling have proven efficacy in various animal models.
 Among all the apoptosis-based drug targets, strategies that
target caspases are at the forefront for blocking apoptosis in
numerous diseases.
 Proof-of-concept data have been obtained in several
experimental models revealing that blockade of apoptosis by
means of caspase inhibitors is a validated therapeutic
strategy
10/29/2021 19
Cont..
 many compounds developed to modulate apoptosis are only
micromolar inhibitors.
 Small-molecule drugs or peptides like caspase inhibitors have
to be optimized to readily penetrate the cells.
 Drugs that selectively target different components of
apoptosis are in clinical trials
 Combination of these novel agents with traditional
chemotherapy seems to be well tolerated and benefit for
patients.
10/29/2021 20
References
1. Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011; 147;
742–758.
2. Wong RSY. Apoptosis in cancer: from pathogenesis to treatment. JECCR. 2011; 30:87.
3. Plati J, Bucur O, Khosravi‐Far R. Dysregulation of apoptotic signaling in cancer. Molecular
mechanisms and therapeutic opportunities. J Cell Biochem. 2008; 104:1124‐1149.
4. Fulda S. Tumor resistance to apoptosis. Int J Cancer. 2009; 124:515‐515.
5. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011; 144:646‐674.
6. Gimenez‐Bonafe P, Tortosa A, Perez‐Tomas R. Overcoming drug resistance by enhancing
apoptosis of tumor cells. Curr Cancer Drug Targ. 2009; 9:320‐340.
7. Yallapu, M.M.; Nagesh, P.K.B.; Jaggi, M.; Chauhan, S.C. Therapeutic applications of curcumin
nanoformulations. AAPS J. 2015, 17, 1341–1356. [CrossRef] [PubMed]
8. Shanmugam, M.K.; Rane, G.; Kanchi, M.M.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.;
Tan, B.K.H.; Kumar, A.P.; Sethi, G. The multifaceted role of curcumin in cancer prevention and
treatment. Molecules 2015, 20, 2728–2769. [CrossRef] [PubMed]
9.U Fischer1 and K Schulze-Osthoff*,Cell Death and Differentiation (2005) 12, 942–961
10/29/2021 21
10/29/2021 22

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Mechanisms and applications of apoptosis based and molecular

  • 1. Dr Satyabrata Sahoo DM Clinical Pharmacology Resident Dept of Clinical & Experimental Pharmacology, CSTM Kolkata 10/29/2021 1
  • 2. Introduction  Apoptosis- Programmed cell death  Orderly and efficient removal of damaged cells following DNA damage or during development  Very complex and involves many signaling pathways  Triggered through caspase-mediated intrinsic and extrinsic pathways  Balance between Pro apoptotic and anti apoptotic regulators important key point in apoptosis.  The dysregulation of apoptosis is a symptom in a wide variety of diseases.  Accelerated apoptosis is found in infertility, immunodeficiency, and acute and chronic degenerative diseases  Delayed or inhibited apoptosis is present in cancer and autoimmunity 10/29/2021 2
  • 4. 10/29/2021 4 Int. J. Mol. Sci. 2018
  • 5. 10/29/2021 5 Int. J. Mol. Sci. 2018
  • 6. 10/29/2021 6 www.impactaging.com 607 AGING, April 2016, Vol. 8 No.4
  • 7. 10/29/2021 7 www.impactaging.com 607 AGING, April 2016, Vol. 8 No.4
  • 8. 10/29/2021 8 Int. J. Mol. Sci. 2018, 19, 448
  • 9. 10/29/2021 9 Apoptosis-based therapies U Fischer and K Schulze-Osthoff
  • 10. 10/29/2021 10 Apoptosis-based therapies U Fischer and K Schulze-Osthoff
  • 11. 10/29/2021 11 Apoptosis-based therapies U Fischer and K Schulze-Osthoff
  • 12. 10/29/2021 12 Apoptosis-based therapies U Fischer and K Schulze-Osthoff
  • 13. 10/29/2021 13 Apoptosis-based therapies U Fischer and K Schulze-Osthoff
  • 14. 10/29/2021 14 Apoptosis-based therapies U Fischer and K Schulze-Osthoff
  • 15. 10/29/2021 15 Apoptosis-based therapies U Fischer and K Schulze-Osthoff
  • 16. 10/29/2021 16 Apoptosis-based therapies U Fischer and K Schulze-Osthoff
  • 17. Novel Therapeutic agents Targeting Apoptosis  Oblimersen sodium-AML  Troglitazone-Advanced prostate cancer  Fenretinide- Rhabdomyosarcoma, ovarian carcinoma  Flavopiridol-AML,SCLC  Gossypol-SCLC,NSCLC  R7112-Advanced solid tumors  APR-246- malignancies, hormone refractory prostate cancer  Dulanermin-Non Hodgkins lymphoma  Tigatuzumab- Breast cancer  Decitabine-Caspase 8 promoters booster 10/29/2021 17
  • 18. Summary  Apoptosis is a cellular procedure regulated by diverse groups of regulatory molecules in which activation of caspase plays a crucial role.  Depending on the molecular target, different strategies are being employed.  Fundamental features of human cancers is evasion of apoptosis.  Leading to tumor progression and resistance to cancer treatment. 10/29/2021 18
  • 19. Cont..  Biologicals including death ligands or agonistic and antagonistic antibodies that inhibit or trigger death receptor signaling have proven efficacy in various animal models.  Among all the apoptosis-based drug targets, strategies that target caspases are at the forefront for blocking apoptosis in numerous diseases.  Proof-of-concept data have been obtained in several experimental models revealing that blockade of apoptosis by means of caspase inhibitors is a validated therapeutic strategy 10/29/2021 19
  • 20. Cont..  many compounds developed to modulate apoptosis are only micromolar inhibitors.  Small-molecule drugs or peptides like caspase inhibitors have to be optimized to readily penetrate the cells.  Drugs that selectively target different components of apoptosis are in clinical trials  Combination of these novel agents with traditional chemotherapy seems to be well tolerated and benefit for patients. 10/29/2021 20
  • 21. References 1. Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell. 2011; 147; 742–758. 2. Wong RSY. Apoptosis in cancer: from pathogenesis to treatment. JECCR. 2011; 30:87. 3. Plati J, Bucur O, Khosravi‐Far R. Dysregulation of apoptotic signaling in cancer. Molecular mechanisms and therapeutic opportunities. J Cell Biochem. 2008; 104:1124‐1149. 4. Fulda S. Tumor resistance to apoptosis. Int J Cancer. 2009; 124:515‐515. 5. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011; 144:646‐674. 6. Gimenez‐Bonafe P, Tortosa A, Perez‐Tomas R. Overcoming drug resistance by enhancing apoptosis of tumor cells. Curr Cancer Drug Targ. 2009; 9:320‐340. 7. Yallapu, M.M.; Nagesh, P.K.B.; Jaggi, M.; Chauhan, S.C. Therapeutic applications of curcumin nanoformulations. AAPS J. 2015, 17, 1341–1356. [CrossRef] [PubMed] 8. Shanmugam, M.K.; Rane, G.; Kanchi, M.M.; Arfuso, F.; Chinnathambi, A.; Zayed, M.E.; Alharbi, S.A.; Tan, B.K.H.; Kumar, A.P.; Sethi, G. The multifaceted role of curcumin in cancer prevention and treatment. Molecules 2015, 20, 2728–2769. [CrossRef] [PubMed] 9.U Fischer1 and K Schulze-Osthoff*,Cell Death and Differentiation (2005) 12, 942–961 10/29/2021 21