Microtubule-associated proteins as targets in cancer chemotherapy

Natural and synthetic compounds that disrupt microtubule dynamics are among the most successful and widely used cancer chemotherapeutic agents. However, lack of reliable markers that predict sensitivity of cancers to these agents and development of resistance remain vexing issues. There is accumulating evidence that a family of cellular proteins that are associated with and alter the dynamics of microtubules can determine sensitivity of cancer cells to microtubule-targeting agents and play a role in tumor cell resistance to these agents. This growing family of microtubule-associated proteins (MAP) includes products of oncogenes, tumor suppressors, and apoptosis regulators, suggesting that alteration of microtubule dynamics may be one of the critical events in tumorigenesis and tumor progression. The objective of this review is to integrate the knowledge on these seemingly unrelated proteins that share a common function and examine their relevance to microtubule-targeting therapies and highlight MAPs-tubulin-drug interactions as a novel avenue for new drug discovery. Based on the available evidence, we propose that rational microtubule-targeting cancer therapeutic approaches should ideally include proteomic profiling of tumor MAPs before administration of microtubule-stabilizing/destabilizing agents preferentially in combination with agents that modulate the expression of relevant MAPs.