Cancer therapeutics: Targeting the apoptotic pathway
Introduction
Apoptosis is a physiological process of programmed cell death that is essential for normal tissue development and haemostasis [1]. It is a process through which damaged, unattached, mutant and aged cells are eliminated. Aberrations in the pathway can lead to a variety of diseases including degenerative and autoimmune disorders and cancer [2]. Apoptosis is one of two major types of cell death that is a highly regulated process with specific and well-described morphological changes. The process was first described in 1842 by Carl Vogt [3] but it was not until 1965 that Lockshin and Williams introduced the concept of ‘programmed cell death’ to describe the coordinated death of larval muscles during their transformation to adult moths [4], [5]. Nearly 10 years later, the term apoptosis was coined by Kerr et al. who described a series of morphological changes, similar to those described by Lockshin and Williams that were associated with the death of a range of tissues [6]. These changes start with compaction of nuclear chromatin, followed by condensation of the cytoplasm, DNA degradation, membrane blebbing and fragmentation of the cell into apoptotic bodies. The apoptotic bodies are taken up by surrounding cells and degraded in their lysosomes in the absence of inflammation [6], [7]. The biochemical changes include double stranded cleavage at the linker regions between nucleosomes, leading to the formation of multiple DNA fragments, phosphatidlyserine externalization and a range of genes and protein expression changes [8], [9].
Also referred to as Type 1 cell death, apoptosis is critical for many physiological processes including cell development, proliferation, differentiation, regulation of the immune system and removal of defective and harmful cells. Aberrant apoptosis is central to many pathological states-enhanced apoptosis has been described in neurodegenerative diseases, Acquired Immuno-Deficiency Syndrome (AIDS), transplant rejection and heart failure [10]. Diminished apoptosis is seen in autoimmune diseases, viral infections and cancer [11].
Targeting components of the apoptotic pathway as a therapeutic approach in cancer is supported by the fact that aberrant apoptosis is central to the growth of tumors and the development of resistance to anti-cancer therapies. Indeed, suppression of apoptosis is a recognized hallmark of cancer [12]. Current anti-cancer treatments including cytotoxic agents and radiotherapy kill cells by inducing apoptosis; mutations of key proteins in the pathway result in the development of resistance to these therapies. Novel approaches to targeting the apoptotic pathway may therefore result in cancer cell death, reverse resistance or induce sensitivity to current treatments.
Section snippets
Apoptosis signalling pathways
There are two known signalling pathways mediating apoptosis: the extrinsic and intrinsic pathways. The extrinsic pathway is mediated by cell surface death receptors, whilst the intrinsic pathway is initiated in the mitochondria. The central regulatory proteins in both pathways are the caspases (cysteine aspartic acid specific proteases). These proteins are synthesized as inactive zymogens which are cleaved into active enzymes in a cascading manner culminating in the activation of what are
Targeting apoptosis: Selected anticancer strategies
The selective modulation of both apoptotic pathways has proven to be a challenge in cancer drug development. Unlike most oncogenes that work by promoting proliferation, Bcl-2 functions by preventing programmed cell death. These proteins therefore provide therapeutic targets where their inhibition can lead to the induction of apoptosis [26]. However, the significant challenge is that many of these targets are protein–protein interactions and difficult to modulate. Despite this, there are several
Development of biomarkers
Targeting apoptosis is a relevant therapeutic approach in anti-cancer drug development as escape from apoptosis is central to cancer progression and the emergence of drug resistance. The use of initial anti-Bcl-2 like proteins in preclinical studies, led to the concept of defining Bcl-2 dependence, and thus aided in the development of compounds targeting this protein superfamily [199]. Indeed several agents targeting both apoptotic pathways have been tested or are undergoing testing in the
Future directions
It has been hypothesized that some cells start closer to the point of commitment to apoptosis then others, and they are likely be more sensitive to pro-apoptotic agents. This can be measured by BH3 profiling, a functional assay that measures mitochondrial response to the measured death signals and provides information about the readiness of the cells to undergo apoptosis [105], [199]. Suspensions of permeabilized cells can be used, but this poses a challenge with solid tumor samples [199].
Conclusion
In conclusion, the central role of apoptosis to tumor progression and resistance to current treatments supports the use of anti-apoptotic agents in combination cancer therapeutics. Further work on determining the structure of component proteins, and the interaction with other signaling pathways may provide a sound platform for designing appropriate biomarker driven clinical trials that will allow for the opportunity to establish these agents in the anti-cancer armamentarium.
K Khan is a Clinical Research Fellow in the Drug Development Unit at the Royal Marsden Hospital. Dr Khan graduated from Dow University of Health Sciences in 2002 and completed training in Medical Oncology in 2013. He is an Honorary Assistant Professor in Aga Khan University Hospital Karachi. Dr. Khan's interests include gastrointestinal cancers and early phase clinical trials. He is a co-author of papers in in peer-reviewed biomedical journals and has written invited chapters for various
References (219)
- et al.
Programmed cell death. 3. Neural control of the breakdown of the intersegmental muscles of silkmoths
J Insect Physiol
(1965) - et al.
Programmed cell death. IV. The influence of drugs on the breakdown of the intersegmental muscles of silkmoths
J Insect Physiol
(1965) - et al.
Cell death: the significance of apoptosis
Int Rev Cytol
(1980) - et al.
Impact of apoptosis in acute rejection episodes after heart transplantation: immunohistochemical examination of right ventricular myocardial biopsies
Transplant Proc
(2008) - et al.
The hallmarks of cancer
Cell
(2000) - et al.
BID, BAX, and lipids cooperate to form supramolecular openings in the outer mitochondrial membrane
Cell
(2002) - et al.
Crystal structure of rat Bcl-xL. Implications for the function of the Bcl-2 protein family
J Biol Chem
(1997) - et al.
Human caspases: activation, specificity, and regulation
J Biol Chem
(2009) - et al.
Cellular inhibitor of apoptosis 1 and 2 are ubiquitin ligases for the apoptosis inducer Smac/DIABLO
J Biol Chem
(2003) - et al.
Structural basis of caspase-7 inhibition by XIAP
Cell
(2001)
Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family
J Biol Chem
Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody rituximab against non-Hodgkin lymphoma xenografts
Blood
Targeting death receptors in cancer with Apo2L/TRAIL
Curr Opin Pharmacol
Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy
Cytokine Growth Factor Rev
Suppression of NF-kappa B survival signaling by nitrosylcobalamin sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL
J Biol Chem
Phase I and pharmacokinetic study of lexatumumab (HGS-ETR2) given every 2 weeks in patients with advanced solid tumors
Ann Oncol
A randomized phase 2 study of paclitaxel and carboplatin with or without conatumumab for first-line treatment of advanced non-small-cell lung cancer
J Thorac Oncol
First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: a phase I/II open-label and double-blind study
Eur J Cancer
A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer
Ann Oncol
A randomized, placebo-controlled phase 2 study of ganitumab or conatumumab in combination with FOLFIRI for second-line treatment of mutant KRAS metastatic colorectal cancer
Ann Oncol
Targeting of Bcl-2 to the mitochondrial outer membrane by a COOH-terminal signal anchor sequence
J Biol Chem
Enhanced antitumour efficacy of gimatecan in combination with Bcl-2 antisense oligonucleotide in human melanoma xenografts
Eur J Cancer
The effect of antisense Bcl-2 oligonucleotides on Bcl-2 protein expression and apoptosis in human bladder transitional cell carcinoma
J Urol
A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors
Ann Oncol
Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia
Blood
A pilot trial of G3139, a Bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer
Ann Oncol
Docetaxel plus oblimersen sodium (Bcl-2 antisense oligonucleotide): an EORTC multicenter, randomized phase II study in patients with castration-resistant prostate cancer
Ann Oncol
A phase II study of Bcl-2 antisense (oblimersen sodium) combined with gemtuzumab ozogamicin in older patients with acute myeloid leukemia in first relapse
Leuk Res
What is apoptosis, and why is it important
BMJ
Apoptosis in cancer: from pathogenesis to treatment
J Exp Clin Cancer Res
Advances in apoptosis research
Proc Nat Acad Sci USA
Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics
Br J Cancer
Apoptosis. Its significance in cancer and cancer therapy
Cancer
Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl
J Exp Med
Apoptosis in autoimmune diseases
Intern Med
Proteases to die for
Genes Dev
BID, BIM, and PUMA are essential for activation of the BAX- and BAK-dependent cell death program
Science
Harakiri, a novel regulator of cell death, encodes a protein that activates apoptosis and interacts selectively with survival-promoting proteins Bcl-2 and Bcl-X(L)
EMBO J
The role of BH3-only proteins in tumor cell development, signaling, and treatment
Genes Cancer
An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif
J Virol
TNF-RII and c-IAP1 mediate ubiquitination and degradation of TRAF2
Nature
Apoptotic cell signaling in cancer progression and therapy
Integr Biol (Camb)
Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family
EMBO Rep
The role of MHC class I allele Mamu-A*07 during SIV(mac)239 infection
Immunogenetics
Emerging applications of the tumor necrosis factor family of ligands and receptors in cancer therapy
J Clin Oncol
Tissue distribution of the death ligand TRAIL and its receptors
J Histochem Cytochem
Safety and antitumor activity of recombinant soluble Apo2 ligand
J Clin Invest
Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity
Nat Med
Ligand-based targeting of apoptosis in cancer: the potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL)
J Clin Oncol
Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL
Cancer Res
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2021, Bioorganic ChemistryCitation Excerpt :These factors cause changes to mitochondrial membrane permeability by promoting pore formation, leading to depolarization of the external mitochondrial membrane, loss of mitochondrial transmembrane potential, and consequent release of apoptotic proteins, such as cytochrome c, Smac/DIABLO, and AIF, to the cytosol. AIF release is regulated by members of the Bcl-2 protein family (such as the antiapoptotic protein Bcl-2 and the proapoptotic protein Bax) [51,58,59]. Apoptosis might be inhibited by survivin, an apoptosis-inhibitory protein overexpressed in most human neoplasms and involved in treatment resistance, which explains its association with poor disease prognosis [60,61].
K Khan is a Clinical Research Fellow in the Drug Development Unit at the Royal Marsden Hospital. Dr Khan graduated from Dow University of Health Sciences in 2002 and completed training in Medical Oncology in 2013. He is an Honorary Assistant Professor in Aga Khan University Hospital Karachi. Dr. Khan's interests include gastrointestinal cancers and early phase clinical trials. He is a co-author of papers in in peer-reviewed biomedical journals and has written invited chapters for various oncology text books. Dr. Khan is member of the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO).
Montserrat Blanco Codesido obtained her medical degree in Santiago de Compostela University in 2001. She completed her specialist training in Medical Oncology in La Paz University Hospital (Madrid) in 2006. During that time she obtained a Masters in Science. She obtained the CNIO’ post-residence grant and worked for more than a year at the Epithelial Carcinogenesis Group under the supervision of Paco Real; she completed her Ph.D. on ‘Prognostic, predictive factors and new targets in locally advanced rectal cancer’ in 2009 at the Autonomous University of Madrid. Between 2009 and 2011, she was a Senior Clinical Fellow in Drug Development at the Drug Development Unit of the Royal Marsden Hospital/Institute of Cancer Research. Currently, she is a consultant in Gregorio Marañón University Hospital specializing in phase I trials and GI cancer. She is an author and co-author of multiple publications and congress presentations.
LR Molife is a Medical Oncologist and Principal Investigator in multiple phase I clinical trials in the Drug Development Unit at the Royal Marsden Hospital/Institute of Cancer Research, London, UK. She graduated in Medicine from the University of Nottingham in 1995 and holds an M.Sc. in Oncology from the University of Nottingham (2004) and an M.D. from the University of Sheffield (2004). Dr Molife has authored or co-authored over 50 original manuscripts, reviews and book chapters, and as a member of the UK Association of Cancer Physicians (ACP), the American Society of Clinical Oncology (ASCO), and the European Society of Medical Oncology (ESMO), has presented original work at national and international meetings.