Broad targeting of resistance to apoptosis in cancer.
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.
Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States; Interim translational Research Institute, Hamad Medical Corporation, Doha, Qatar. Electronic address: mohammar@karmanos.org.
Ramzi M
RM
Mohammad
Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States.
Irfana
I
Muqbil
Getting to Know Cancer, Truro, Nova Scotia, Canada.
Leroy
L
Lowe
C-SET, [Jackson, #229] State University, Jackson, MS, United States.
Clement
C
Yedjou
Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan.
Hsue-Yin
HY
Hsu
Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Liang-Tzung
LT
Lin
Department of Pathology and Cell Biology, Columbia University, New York City, NY, United States.
Markus David
MD
Siegelin
Dipartimento di Scienze per la Qualità della Vita Alma Mater Studiorum-Università di Bologna, Italy.
Carmela
C
Fimognari
Moffit Cancer Center, University of South Florida College of Medicine, Tampa, FL, United States.
Nagi B
NB
Kumar
Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States; Departments of Pharmacology and Pathology, Karmanos Cancer Institute, Detroit MI, United States.
Q Ping
QP
Dou
The School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, China.
Huanjie
H
Yang
Sanus Bioscience, San Diego, CA, USA.
Abbas K
AK
Samadi
Institute of Food Sciences National Research Council, Avellino, Italy.
Gian Luigi
GL
Russo
Institute of Food Sciences National Research Council, Avellino, Italy.
Carmela
C
Spagnuolo
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States.
Swapan K
SK
Ray
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States.
Mrinmay
M
Chakrabarti
Mor-NuCo, Inc, Purdue Research Park, West Lafayette, IN, United States.
James D
JD
Morre
Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom.
Helen M
HM
Coley
Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan.
Kanya
K
Honoki
Department of Orthopedic Surgery, Nara Medical University, Kashihara, Japan.
Hiromasa
H
Fujii
Department of Physics, School of Applied Mathematical and Physical Sciences, National Technical University of Athens, Zografou 15780, Athens, Greece.
Alexandros G
AG
Georgakilas
Department of Experimental and Clinical Medicine, university of florence, Italy.
Amedeo
A
Amedei
Department of Experimental and Clinical Medicine, university of florence, Italy.
Elena
E
Niccolai
Department of Biology, College of Science, UAE University, United Arab Emirates; Faculty of Science, Cairo University, Egypt.
Amr
A
Amin
Department of Chemistry, College of Science, UAE University, United Arab Emirates.
S Salman
SS
Ashraf
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
William G
WG
Helferich
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, United States.
Xujuan
X
Yang
Department of BioMedical Sciences, School of Medicine Creighton University, Omaha NE, United States.
Chandra S
CS
Boosani
School of Chemical and Bio Technology, SASTRA University, Thanjavur, India.
Gunjan
G
Guha
School of Chemical and Bio Technology, SASTRA University, Thanjavur, India.
Dipita
D
Bhakta
Department of Biology, University of Rome "Tor Vergata", Italy.
Maria Rosa
MR
Ciriolo
Department of Biology, University of Rome "Tor Vergata", Italy.
Katia
K
Aquilano
Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey, United Kingdom.
Sophie
S
Chen
Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue, West Lafayette, IN, United States.
Sulma I
SI
Mohammed
Institute of Cancer Sciences, University of Glasgow, Glasgow, Ireland.
W Nicol
WN
Keith
Institute of Cancer Sciences, University of Glasgow, Glasgow, Ireland.
Alan
A
Bilsland
Department of Pathology, New York Medical College, Valhalla, NY, United States.
Dorota
D
Halicka
Mayo Graduate School, Mayo Medical School, Mayo Clinic Medical Scientist Training Program, Rochester, MN, United States.
Somaira
S
Nowsheen
Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, United States.
Asfar S
AS
Azmi
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D001343:Autophagy / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D000970:Antineoplastic Agents
Apoptosis; Apoptosis evasion; Autophagy; Necrosis; Nuclear transporters, natural chemopreventive agents