期刊
EXPERT OPINION ON THERAPEUTIC TARGETS
卷 17, 期 1, 页码 61-75出版社
TAYLOR & FRANCIS LTD
DOI: 10.1517/14728222.2013.733001
关键词
apoptosis; BH3 domain; chemotherapy resistance; Mcl-1; radiation resistance
资金
- National Institutes of Health [1R01 CA097318, 1R01 CA127641, R01 CA138540, R01 CA149668, R01 CA168517]
- National Foundation for Cancer Research (NFCR) [1R01 CA108520]
- James S. McDonnell Foundation
- National Foundation for Cancer Research (NFCR)
- Samuel Waxman Cancer Research Foundation (SWCRF)
- Army DoD [W81XWH-11-1-0480]
- California Institute for Regenerative Medicine [TR2-01789]
- NATIONAL CANCER INSTITUTE [R01CA097318, R01CA141703, R01CA127641, R01CA168517, R01CA138540, R01CA149668, R01CA150214, R01CA108520] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK052825] Funding Source: NIH RePORTER
Introduction: Programmed cell death is well-orchestrated process regulated by multiple pro-apoptotic and anti-apoptotic genes, particularly those of the Bcl-2 gene family. These genes are well documented in cancer with aberrant expression being strongly associated with resistance to chemotherapy and radiation. Areas covered: This review focuses on the resistance induced by the Bcl-2 family of anti-apoptotic proteins and current therapeutic interventions currently in preclinical or clinical trials that target this pathway. Major resistance mechanisms that are regulated by Bcl-2 family proteins and potential strategies to circumvent resistance are also examined. Although antisense and gene therapy strategies are used to nullify Bcl-2 family proteins, recent approaches use small molecule inhibitors (SMIs) and peptides. Structural similarity of the Bcl-2 family of proteins greatly favors development of inhibitors that target the BH3 domain, called BH3 mimetics. Expert opinion: Strategies to specifically identify and inhibit critical determinants that promote therapy resistance and tumor progression represent viable approaches for developing effective cancer therapies. From a clinical perspective, pretreatment with novel, potent Bcl-2 inhibitors either alone or in combination with conventional therapies hold significant promise for providing beneficial clinical outcomes. Identifying SMIs with broader and higher affinities for inhibiting all of the Bcl-2 pro-survival proteins will facilitate development of superior cancer therapies.
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