Pro-Oxidant Milieu Blunts Scissors: Insight into Tumor Progression, Drug Resistance, and Novel Druggable Targets

Shazib      Pervaiz

Abstract

Apoptosis is an essential and highly conserved process for the maintenance of tissue homeostasis and involves a programmed series of events for the removal of effete, damaged, or mutated cells. Although, activation of caspases underscores the classical signaling cascade during apoptotic execution the role of caspase-independent mechanisms in apoptosis has also gained recognition. It is now well established that apoptotic execution is an inherent tumor suppressor mechanism and failure of apoptosis invariably leads to the acquisition of the transformed phenotype. Indeed, resistance to apoptosis is an essential acquired trait that facilitates the processes of tumor initiation and progression. As a matter of fact, efficient death execution could be a critical even at an earlier stage to inhibit tumor promotion. Interestingly, there is a school of thought supported by strong data that an altered redox status and intracellular milieu of cells could provide the seeding ground for tumor promotion and initiation, and at a latter stage tumor maintenance/progression, by blunting cell death signaling. These findings have not only enhanced our understanding of the processes of carcinogenesis and drug resistance but, more importantly provide novel targets for designing strategies to overcome the problem of apoptosis resistance in tumor cells. This review focuses on the pathways of apoptotic execution, and discusses the role of intracellular redox status on cell survival and death signaling in tumor cells.

Keywords: death effector domains (DED), reactive oxygen species (ROS), oligomerization, pro-oxidant state, Carcinogenesis

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