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Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies

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Abstract

Cancer is a primary cause of human fatality and conventional cancer therapies, e.g., chemotherapy, are often associated with adverse side-effects, tumor drug-resistance, and recurrence. Molecularly targeted therapy, composed of small-molecule inhibitors and immunotherapy (e.g., monoclonal antibody and cancer vaccines), is a less harmful alternative being more effective against cancer cells whilst preserving healthy tissues. Drug-resistance, however, caused by negative regulation of cell death signaling pathways, is still a challenge. Circumvention of negative regulators of cell death pathways or development of predictive and response biomarkers is, therefore, quintessential. This review critically discusses the current state of knowledge on targeting negative regulators of cell death signaling pathways including apoptosis, ferroptosis, necroptosis, autophagy, and anoikis and evaluates the recent advances in clinical and preclinical research on biomarkers of negative regulators. It aims to provide a comprehensive platform for designing efficacious polytherapies including novel agents for restoring cell death signaling pathways or targeting alternative resistance pathways to improve the chances for antitumor responses. Overall, it is concluded that nonapoptotic cell death pathways are a potential research arena for drug discovery, development of novel biomarkers and targeted therapies.

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Authors and Affiliations

  1. Centre for Biodiscovery and Molecular Development of Therapeutics, James Cook University, Townsville, QLD, 4811, Australia

    Ali Razaghi, Kirsten Heimann & Patrick M. Schaeffer

  2. Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada

    Spencer B. Gibson

  3. Departments of Biochemistry and Medical Genetics and Immunology, University of Manitoba, Winnipeg, MB, Canada

    Spencer B. Gibson

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10495_2018_1440_MOESM1_ESM.mp4

Supplementary Video 1. Anti-apoptotic Bcl-xl protein negatively regulates Fas-mediated apoptosis. Subsequently, SMI deactivates Bcl-xl and unblocks the signal transduction pathway, restoring apoptosis. Bax, Bcl-2-associated X protein; BID, BH3 interacting-domain death agonist; Casp-8, caspase-8; CYT-C, cytochrome-c; FADD, Fas-associated protein with death domain; FasL, Fas ligand; RIP, receptor interacting protein; SMI, small-molecule inhibitor; tBID, truncated BID (MP4 7150 KB)

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Razaghi, A., Heimann, K., Schaeffer, P.M. et al. Negative regulators of cell death pathways in cancer: perspective on biomarkers and targeted therapies. Apoptosis 23, 93–112 (2018). https://doi.org/10.1007/s10495-018-1440-4

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