Microtubule-targeted anticancer agents and apoptosis

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Abstract
Over the past decade, significant progress has been made in our understanding of the biology of microtubule (MT) assembly into the mitotic spindle during mitosis and the molecular signaling and execution of the various pathways to apoptosis. In the same period, the microtubule-targeted tubulin-polymerizing agents (MTPAs), notably paclitaxel and taxotere, have come to occupy a central role in the treatment of a variety of human epithelial cancers. Following their binding to B-tubulin, MTPAs inhibit MT dynamic instability, cell cycle G2/M phase transition and mitotic arrest of cancer cells. MTPA-induced anti-MT and cell cycle effects trigger the molecular signaling for the mitochondrial pathway of apoptosis. This triggering is orchestrated through different molecular links and determined by the threshold for apoptosis that is set and controlled diversely in various cancer types. The complexity and regulatory potential of the links and the apoptosis threshold are integral to the transformed biology of the cancer cell. The emerging understanding of this biology and how it is influenced by treatment with MTPAs has highlighted novel strategies to further enhance the antitumor activity and overcome resistance to MTPA-induced apoptosis in cancer cells.