Molecular Mechanisms of Taxol for Induction of Cell Death in Glioblastomas
Glioblastomas are the most frequent and devastating brain tumors in adults. Molecular and cytogenetic studies of glioblastomas have revealed a wide variety of deregulated genes that are associated with cell cycles, DNA repair, apoptosis, cell migration, invasion, and angiogenesis with little translational success. Understanding the molecular mechanisms of these deregulated genes can provide a rationale for targeting specific pathways of repair, signaling, and angiogenesis. Taxol, one of the most potent anti-neoplastic drugs, strongly binds to the N-terminal region of β-tubulin to prevent tumor cell division and induce cell death. The effects of taxol may vary depending on cell type and drug concentration. At lower concentrations ranging from 10 to 100 nM, taxol induces phosphorylation of Bcl-2, which in turn triggers mitochondrial release of cytochrome c, cleavage of pro-caspases and poly(ADP-ribose) polymerase (PARP), leading to apoptotic death. Phosphorylation of Bcl-2 also inhibits the ability of Bcl-2 to increase intracellular free [Ca2+], which triggers calpain-mediated apoptosis. At higher concentrations, taxol induces cell death due to stabilization of microtubules and mitochondrial collapse, leading to cell cycle arrest at G2/M phase. Disruption of the mitotic spindle activates a number of signaling pathways, with consequences that may protect the cell. The cells arrested in mitosis exhibit no signal for apoptosis but have an increased expression of survivin, an inhibitor of apoptosis. A thorough understanding of the molecular signaling events associated with taxol-mediated cell cycle arrest is essential, particularly in regard to its potential in combination therapy, where multiple therapeutic agents are used to enhance the efficacy of treatment in controlling cancer cells. In this chapter, we present an overview of the latest research on the molecular signaling mechanisms of taxol, events leading to apoptosis, potential of taxol in combination chemotherapy, and emerging gene therapy.
KeywordsApoptosis Combination therapy Gene therapy Glioblastomas Taxol
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