Broad targeting of resistance to apoptosis in cancer.

Abstract

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

• Authors: Ramzi M Mohammad, Irfana Muqbil, Leroy Lowe, Clement Yedjou, Hsue-Yin Hsu, Liang-Tzung Lin, Markus David Siegelin, Carmela Fimognari, Nagi B Kumar, Q Ping Dou, Huanjie Yang, Abbas K Samadi, Gian Luigi Russo, Carmela Spagnuolo, Swapan K Ray, Mrinmay Chakrabarti, James D Morre, Helen M Coley, Kanya Honoki, Hiromasa Fujii, Alexandros G Georgakilas, Amedeo Amedei, Elena Niccolai, Amr Amin, S Salman Ashraf, William G Helferich, Xujuan Yang, Chandra S Boosani, Gunjan Guha, Dipita Bhakta, Maria Rosa Ciriolo, Katia Aquilano, Sophie Chen, Sulma I Mohammed, W Nicol Keith, Alan Bilsland, Dorota Halicka, Somaira Nowsheen, Asfar S Azmi
• Journal: Seminars in cancer biology (Semin Cancer Biol) Vol. 35 Suppl Pg. S78-S103 (Dec 2015) ISSN: 1096-3650 [Electronic] England
• PMID: 25936818 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents

Topics

• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects, genetics)
• Autophagy (genetics)
• Cell Proliferation (genetics)
• Drug Resistance, Neoplasm (genetics)
• Humans
• Molecular Targeted Therapy
• Neoplasms (drug therapy, genetics, pathology)
• Signal Transduction (drug effects, genetics)