BCL-2 protein family: attractive targets for cancer therapy

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2023 Feb;28(1-2):20-38.

doi: 10.1007/s10495-022-01780-7.

Epub 2022 Nov 7.

Deeksha Kaloni   1   2 ,

Sarah T Diepstraten   1 ,

Andreas Strasser   1   2 ,

Gemma L Kelly   3   4

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Affiliations

1 Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.

2 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.

3 Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. gkelly@wehi.edu.au.

4 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. gkelly@wehi.edu.au.

PMID: 36342579

PMCID: PMC9950219

DOI: 10.1007/s10495-022-01780-7

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Deeksha Kaloni  et al.

Apoptosis .

2023 Feb .

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2023 Feb;28(1-2):20-38.

doi: 10.1007/s10495-022-01780-7.

Epub 2022 Nov 7.

Authors

Deeksha Kaloni   1   2 ,

Sarah T Diepstraten   1 ,

Andreas Strasser   1   2 ,

Gemma L Kelly   3   4

Affiliations

1 Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.

2 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.

3 Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. gkelly@wehi.edu.au.

4 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. gkelly@wehi.edu.au.

PMID: 36342579

PMCID: PMC9950219

DOI: 10.1007/s10495-022-01780-7

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Abstract

Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in diverse malignancies. The critical role of the pro-survival and pro-apoptotic BCL-2 family proteins in the regulation of apoptosis makes them attractive targets for the development of agents for the treatment of cancer. This review describes the roles of the various pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function and how defects in the control of apoptosis promote the development and therapy resistance of cancer. Finally, we discuss the development of inhibitors of pro-survival BCL-2 proteins, termed BH3-mimetic drugs, as novel agents for cancer therapy.

Keywords: Apoptosis; BCL-2 protein family; BH3-mimetic drugs; BH3-only proteins; Pro-apoptotic BCL-2 family members; Pro-survival BCL-2 proteins.

© 2022. The Author(s).

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Conflict of interest statement

All authors are employees of WEHI which receives milestone and royalty payments related to venetoclax. AS and GLK have received research funding from Servier. AS is a consultant for Genentech and Servier.

Figures

Fig. 1

The intrinsic pathway of apoptotic…

Fig. 1

The intrinsic pathway of apoptotic cell death is controlled by the BCL-2 protein…

Fig. 2

Potential strategies targeting the intrinsic…

Fig. 2

Potential strategies targeting the intrinsic apoptotic pathway either by directly targeting the pro-apoptotic…

See this image and copyright information in PMC

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References

Voss AK, Strasser A (2020) The essentials of developmental apoptosis F1000Research 9. 10.12688/f1000research.21571.1 - PMC - PubMed

Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267:1456–1462. doi: 10.1126/science.7878464. - DOI - PubMed

Strasser A, Harris AW, Huang DCS, Krammer PH, Cory S (1995) Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J 14:6136–6147. doi:0.1002/j.1460-2075.1995.tb00304.x - PMC - PubMed

Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;281:1322–1326. doi: 10.1126/science.281.5381.1322. - DOI - PubMed

Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9:47–59. doi: 10.1038/nrm2308. - DOI - PubMed

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Search in PubMed. Search in NLM Catalog. Add to Search. . 2023 Feb;28(1-2):20-38. doi: 10.1007/s10495-022-01780-7. Epub 2022 Nov 7. Deeksha Kaloni   1   2 , Sarah T Diepstraten   1 , Andreas Strasser   1   2 , Gemma L Kelly   3   4. Expand. Affiliations. 1 Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. 2 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. 3 Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. gkelly@wehi.edu.au. 4 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. gkelly@wehi.edu.au. PMID: 36342579. PMCID: PMC9950219. DOI: 10.1007/s10495-022-01780-7. Free PMC article. Deeksha Kaloni  et al. Apoptosis . 2023 Feb . Free PMC article. Show details. Display options. Format. Search in PubMed. Search in NLM Catalog. Add to Search. . 2023 Feb;28(1-2):20-38. doi: 10.1007/s10495-022-01780-7. Epub 2022 Nov 7. Authors. Deeksha Kaloni   1   2 , Sarah T Diepstraten   1 , Andreas Strasser   1   2 , Gemma L Kelly   3   4. Affiliations. 1 Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. 2 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. 3 Blood Cells and Blood Cancer Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. gkelly@wehi.edu.au. 4 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. gkelly@wehi.edu.au. PMID: 36342579. PMCID: PMC9950219. DOI: 10.1007/s10495-022-01780-7. Cite. Display options. Format. Abstract. Acquired resistance to cell death is a hallmark of cancer. The BCL-2 protein family members play important roles in controlling apoptotic cell death. Abnormal over-expression of pro-survival BCL-2 family members or abnormal reduction of pro-apoptotic BCL-2 family proteins, both resulting in the inhibition of apoptosis, are frequently detected in diverse malignancies. The critical role of the pro-survival and pro-apoptotic BCL-2 family proteins in the regulation of apoptosis makes them attractive targets for the development of agents for the treatment of cancer. This review describes the roles of the various pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function and how defects in the control of apoptosis promote the development and therapy resistance of cancer. Finally, we discuss the development of inhibitors of pro-survival BCL-2 proteins, termed BH3-mimetic drugs, as novel agents for cancer therapy. Keywords: Apoptosis; BCL-2 protein family; BH3-mimetic drugs; BH3-only proteins; Pro-apoptotic BCL-2 family members; Pro-survival BCL-2 proteins. © 2022. The Author(s). PubMed Disclaimer. Conflict of interest statement. All authors are employees of WEHI which receives milestone and royalty payments related to venetoclax. AS and GLK have received research funding from Servier. AS is a consultant for Genentech and Servier. Figures. Fig. 1. The intrinsic pathway of apoptotic… Fig. 1. The intrinsic pathway of apoptotic cell death is controlled by the BCL-2 protein… Fig. 2. Potential strategies targeting the intrinsic… Fig. 2. Potential strategies targeting the intrinsic apoptotic pathway either by directly targeting the pro-apoptotic… See this image and copyright information in PMC. Similar articles. What can we learn from mice lacking pro-survival BCL-2 proteins to advance BH3 mimetic drugs for cancer therapy? Brinkmann K, Ng AP, de Graaf CA, Strasser A. Brinkmann K, et al. Cell Death Differ. 2022 Jun;29(6):1079-1093. doi: 10.1038/s41418-022-00987-0. Epub 2022 Apr 6. Cell Death Differ. 2022. PMID: 35388168 Free PMC article. Review. Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer. D'Aguanno S, Del Bufalo D. D'Aguanno S, et al. Cells. 2020 May 21;9(5):1287. doi: 10.3390/cells9051287. Cells. 2020. PMID: 32455818 Free PMC article. Review. The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. Kazi A, Sun J, Doi K, Sung SS, Takahashi Y, Yin H, Rodriguez JM, Becerril J, Berndt N, Hamilton AD, Wang HG, Sebti SM. Kazi A, et al. J Biol Chem. 2011 Mar 18;286(11):9382-92. doi: 10.1074/jbc.M110.203638. Epub 2010 Dec 9. J Biol Chem. 2011. PMID: 21148306 Free PMC article. BH3 mimetics induce apoptosis independent of DRP-1 in melanoma. Mukherjee N, Strosnider A, Vagher B, Lambert KA, Slaven S, Robinson WA, Amato CM, Couts KL, Bemis JGT, Turner JA, Norris DA, Shellman YG. Mukherjee N, et al. Cell Death Dis. 2018 Sep 5;9(9):907. doi: 10.1038/s41419-018-0932-z. Cell Death Dis. 2018. PMID: 30185782 Free PMC article. BCL-2 family isoforms in apoptosis and cancer. Warren CFA, Wong-Brown MW, Bowden NA. Warren CFA, et al. Cell Death Dis. 2019 Feb 21;10(3):177. doi: 10.1038/s41419-019-1407-6. Cell Death Dis. 2019. PMID: 30792387 Free PMC article. Review. See all similar articles. Cited by. Protein disulfide isomerase family member 4 promotes triple-negative breast cancer tumorigenesis and radiotherapy resistance through JNK pathway. Tao J, Xue C, Cao M, Ye J, Sun Y, Chen H, Guan Y, Zhang W, Zhang W, Yao Y. Tao J, et al. Breast Cancer Res. 2024 Jan 2;26(1):1. doi: 10.1186/s13058-023-01758-6. Breast Cancer Res. 2024. PMID: 38167446 Free PMC article. Expanding Roles of the E2F-RB-p53 Pathway in Tumor Suppression. Zhou Y, Nakajima R, Shirasawa M, Fikriyanti M, Zhao L, Iwanaga R, Bradford AP, Kurayoshi K, Araki K, Ohtani K. Zhou Y, et al. Biology (Basel). 2023 Dec 11;12(12):1511. doi: 10.3390/biology12121511. Biology (Basel). 2023. PMID: 38132337 Free PMC article. Review. TRAIL-Sensitizing Effects of Flavonoids in Cancer. Luiz-Ferreira A, Pacifico T, Cruz AC, Laudisi F, Monteleone G, Stolfi C. Luiz-Ferreira A, et al. Int J Mol Sci. 2023 Nov 22;24(23):16596. doi: 10.3390/ijms242316596. Int J Mol Sci. 2023. PMID: 38068921 Free PMC article. Review. Mechanisms of action of the BCL-2 inhibitor venetoclax in multiple myeloma: a literature review. Cao Q, Wu X, Zhang Q, Gong J, Chen Y, You Y, Shen J, Qiang Y, Cao G. Cao Q, et al. Front Pharmacol. 2023 Nov 6;14:1291920. doi: 10.3389/fphar.2023.1291920. eCollection 2023. Front Pharmacol. 2023. PMID: 38026941 Free PMC article. Review. Potential Associations between Vascular Biology and Hodgkin's Lymphoma: An Overview. Rodrigues WF, Miguel CB, Abreu MCM, Neto JM, Oliveira CJF. Rodrigues WF, et al. Cancers (Basel). 2023 Nov 6;15(21):5299. doi: 10.3390/cancers15215299. Cancers (Basel). 2023. PMID: 37958472 Free PMC article. Review. See all "Cited by" articles. References. Voss AK, Strasser A (2020) The essentials of developmental apoptosis F1000Research 9. 10.12688/f1000research.21571.1 - PMC - PubMed. Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267:1456–1462. doi: 10.1126/science.7878464. - DOI - PubMed. Strasser A, Harris AW, Huang DCS, Krammer PH, Cory S (1995) Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J 14:6136–6147. doi:0.1002/j.1460-2075.1995.tb00304.x - PMC - PubMed. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;281:1322–1326. doi: 10.1126/science.281.5381.1322. - DOI - PubMed. Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9:47–59. doi: 10.1038/nrm2308. - DOI - PubMed. Publication types. Review Actions Search in PubMed Search in MeSH Add to Search. MeSH terms. Apoptosis Regulatory Proteins / metabolism Actions Search in PubMed Search in MeSH Add to Search. Apoptosis* / physiology Actions Search in PubMed Search in MeSH Add to Search. Humans Actions Search in PubMed Search in MeSH Add to Search. Neoplasms* / drug therapy Actions Search in PubMed Search in MeSH Add to Search. Neoplasms* / genetics Actions Search in PubMed Search in MeSH Add to Search. Neoplasms* / metabolism Actions Search in PubMed Search in MeSH Add to Search. Proto-Oncogene Proteins c-bcl-2 / metabolism Actions Search in PubMed Search in MeSH Add to Search. Substances. Proto-Oncogene Proteins c-bcl-2 Actions Search in PubMed Search in MeSH Add to Search. Apoptosis Regulatory Proteins Actions Search in PubMed Search in MeSH Add to Search. Related information. MedGen. LinkOut - more resources. Full Text Sources Europe PubMed Central PubMed Central Springer. Medical MedlinePlus Health Information.