Abstract
Targeting the mitotic pathways of rapidly proliferating tumor cells has been an effective strategy in traditional cancer therapy. Chemotherapeutics such as taxanes and vinca alkaloids, which disrupt microtubule function, have enjoyed clinical success; however, the accompanying side effects, toxicity and multi drug resistance remain as serious concerns. The emerging classes of inhibitors targeting mitotic kinases and proteasome face their own set of challenges. It is hoped that elucidation of the regulatory interface between mitotic checkpoints, mitochondria and mitotic death will aid the development of more efficacious anti-mitotic agents and improved treatment protocols. The links between the spindle assembly checkpoint (SAC) and mitochondrial dynamics that control the progression of anti-mitotic agent-induced apoptosis have been under investigation for several years and the functional integration of these various signaling networks is now beginning to emerge. In this review, we highlight current research on the regulation of SAC, the death pathway and mitochondria with particular focus on their regulatory interconnections.
Highlights
Mitosis (M phase) is characterized by a set of highly orchestrated cellular events
A direct consequence of an exceedingly prolonged mitosis is the activation of the death pathway that resembles, in its characteristics, the intrinsic/mitochondrial pathway of programed cell death or apoptosis
The activation of pro-apoptotic proteins signals the recruitment and oligomerization of the Bcl-2 effector proteins Bax (Bcl-2associated X protein) and Bak (Bcl-2 antagonist or killer) on mitochondria. This leads to the mitochondrial outer membrane permeabilization (MOMP), triggering the release of proapoptotic mitochondrial intermembrane-space proteins such as cytochrome c, which in turn facilitates the formation of apoptosome [constituents: cytochrome c, Apaf-1 and procaspase-9]
Summary
Targeting the mitotic pathways of rapidly proliferating tumor cells has been an effective strategy in traditional cancer therapy. Chemotherapeutics such as taxanes and vinca alkaloids, which disrupt microtubule function, have enjoyed clinical success; the accompanying side effects, toxicity and multi drug resistance remain as serious concerns. It is hoped that elucidation of the regulatory interface between mitotic checkpoints, mitochondria and mitotic death will aid the development of more efficacious anti-mitotic agents and improved treatment protocols. The links between the spindle assembly checkpoint (SAC) and mitochondrial dynamics that control the progression of anti-mitotic agent-induced apoptosis have been under investigation for several years and the functional integration of these various signaling networks is beginning to emerge.
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