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Review

Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance

1
European University Research Center, Nicosia 2404, Cyprus
2
Tumor Microenvironment, Metastasis and Experimental Therapeutics Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus
3
Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus
4
Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, 15784 Athens, Greece
5
Department of Medical Pharmacology, Cancer immunology and Immunotherapy Unit, Medical School, Akdeniz University, Antalya 07058, Turkey
*
Author to whom correspondence should be addressed.
Academic Editor: Claudia M. Kowolik
Cancers 2021, 13(17), 4363; https://doi.org/10.3390/cancers13174363
Received: 29 July 2021 / Revised: 21 August 2021 / Accepted: 26 August 2021 / Published: 28 August 2021
Despite recent therapeutic advances against cancer, many patients do not respond well or respond poorly, to treatment and develop resistance to more than one anti-cancer drug, a term called multi-drug resistance (MDR). One of the main factors that contribute to MDR is the deregulation of apoptosis or programmed cell death. Herein, we describe the major apoptotic pathways and discuss how pro-apoptotic and anti-apoptotic proteins are modified in cancer cells to convey drug resistance. We also focus on our current understanding related to the interactions between survival and cell death pathways, as well as on mechanisms underlying the balance shift towards cancer cell growth and drug resistance. Moreover, we highlight the role of the tumor microenvironment components in blocking apoptosis in MDR tumors, and we discuss the significance and potential exploitation of epigenetic modifications for cancer treatment. Finally, we summarize the current and future therapeutic approaches for overcoming MDR.
The ability of tumor cells to evade apoptosis is established as one of the hallmarks of cancer. The deregulation of apoptotic pathways conveys a survival advantage enabling cancer cells to develop multi-drug resistance (MDR), a complex tumor phenotype referring to concurrent resistance toward agents with different function and/or structure. Proteins implicated in the intrinsic pathway of apoptosis, including the Bcl-2 superfamily and Inhibitors of Apoptosis (IAP) family members, as well as their regulator, tumor suppressor p53, have been implicated in the development of MDR in many cancer types. The PI3K/AKT pathway is pivotal in promoting survival and proliferation and is often overactive in MDR tumors. In addition, the tumor microenvironment, particularly factors secreted by cancer-associated fibroblasts, can inhibit apoptosis in cancer cells and reduce the effectiveness of different anti-cancer drugs. In this review, we describe the main alterations that occur in apoptosis-and related pathways to promote MDR. We also summarize the main therapeutic approaches against resistant tumors, including agents targeting Bcl-2 family members, small molecule inhibitors against IAPs or AKT and agents of natural origin that may be used as monotherapy or in combination with conventional therapeutics. Finally, we highlight the potential of therapeutic exploitation of epigenetic modifications to reverse the MDR phenotype. View Full-Text
Keywords: apoptosis; Bcl-2 family of proteins; cancer associated fibroblasts; cancer therapy; caspase-dependent death; epigenetic modifications; multi-drug resistance; PI3K/AKT pathway; tumor-microenvironment apoptosis; Bcl-2 family of proteins; cancer associated fibroblasts; cancer therapy; caspase-dependent death; epigenetic modifications; multi-drug resistance; PI3K/AKT pathway; tumor-microenvironment
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MDPI and ACS Style

Neophytou, C.M.; Trougakos, I.P.; Erin, N.; Papageorgis, P. Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance. Cancers 2021, 13, 4363. https://doi.org/10.3390/cancers13174363

AMA Style

Neophytou CM, Trougakos IP, Erin N, Papageorgis P. Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance. Cancers. 2021; 13(17):4363. https://doi.org/10.3390/cancers13174363

Chicago/Turabian Style

Neophytou, Christiana M., Ioannis P. Trougakos, Nuray Erin, and Panagiotis Papageorgis. 2021. "Apoptosis Deregulation and the Development of Cancer Multi-Drug Resistance" Cancers 13, no. 17: 4363. https://doi.org/10.3390/cancers13174363

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