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Broad targeting of resistance to apoptosis in cancer
Ramzi M Mohammad1, Irfana Muqbil2, Leroy Lowe3
1Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States; Interim translational Research Institute, Hamad Medical Corporation, Doha, Qatar.
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.
Insights
Cancer cells evade apoptosis, programmed cell death, through complex resistance mechanisms. This review explores key targets and novel strategies to overcome apoptosis resistance for improved cancer therapy outcomes.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Apoptosis (programmed cell death) is crucial for eliminating aged cells, and anti-cancer therapies often exploit this pathway.
- Cancer cells develop resistance to apoptosis by dysregulating signaling pathways, leading to tumor survival, therapeutic resistance, and recurrence.
- Apoptosis resistance is a complex phenomenon involving interactions between various molecules and signaling pathways.
Purpose of the Study:
- To comprehensively review the factors contributing to apoptosis resistance in cancer.
- To highlight the shortcomings of current therapeutic strategies in overcoming apoptosis resistance.
- To present a broad-spectrum strategy with novel therapeutic approaches to overcome cell death resistance.
Main Methods:
- Literature review of factors contributing to apoptosis resistance.
- Analysis of key resistance targets including Bcl-2/Mcl-1 proteins, autophagy, and proteasome pathways.
- Discussion of novel therapeutic agents and strategies to overcome resistance.
Main Results:
- Identified key resistance mechanisms: Bcl-2/Mcl-1 proteins, autophagy, necrosis/necroptosis, heat shock proteins, proteasome pathway, epigenetics, and nuclear export signaling.
- Highlighted limitations of existing anti-cancer therapies in addressing apoptosis resistance.
- Presented a multi-pronged therapeutic strategy involving agents like gossypol, epigallocatechin-3-gallate, UMI-77, triptolide, and selinexor.
Conclusions:
- Understanding apoptosis resistance mechanisms is critical for developing effective cancer treatments.
- Targeting multiple resistance pathways simultaneously offers a promising strategy to overcome therapeutic resistance.
- This review provides a roadmap for designing novel anti-cancer strategies to improve patient outcomes by overcoming apoptosis resistance.
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