, Volume 23, Issue 2, pp 93–112 | Cite as

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

  • Ali RazaghiEmail author
  • Kirsten Heimann
  • Patrick M. Schaeffer
  • Spencer B. Gibson


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.


Cancer targeted therapy Drug resistance Cell death pathway Negative regulator Biomarker Immunotherapy 


Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10495_2018_1440_MOESM1_ESM.mp4 (7 mb)
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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ali Razaghi
    • 1
    Email author
  • Kirsten Heimann
    • 1
  • Patrick M. Schaeffer
    • 1
  • Spencer B. Gibson
    • 2
    • 3
  1. 1.Centre for Biodiscovery and Molecular Development of TherapeuticsJames Cook UniversityTownsvilleAustralia
  2. 2.Research Institute in Oncology and HematologyCancerCare ManitobaWinnipegCanada
  3. 3.Departments of Biochemistry and Medical Genetics and ImmunologyUniversity of ManitobaWinnipegCanada

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