Role of tumor hypoxia in acquisition of resistance to microtubule-stabilizing drugs.

Microtubules, an important cytoskeletal protein involved in mitotic and non-mitotic functions of cells, are important targets in cancer therapy. Microtubule-stabilizing drugs like the taxanes are critical adjuvant and palliative first-line therapies for the treatment of early, advanced and metastatic solid tumors of different lineages. Their adverse on- and off-target effects and high susceptibility to multidrug resistance, however, are major challenges encountered in the clinic in the treatment of solid cancers. Although biochemical resistance to microtubule-stabilizing drugs has been well characterized, molecular mechanisms that contribute to clinical resistance to taxanes in solid tumors still remain poorly understood and uncontrolled. The heterogeneous tumor microenvironment leads to greater diversity of resistance mechanisms to taxanes. Tumor hypoxia, a prominent feature of solid tumors, results in a broad range of effects on a number of cellular pathways and is one of the major contributors to the development of resistance to not only microtubule-stabilizing drugs but also other anticancer drugs. In this review, we highlight the potential role of hypoxia in the development of resistance to taxanes through mechanisms that involve altering the cell cycle, changing the properties of microtubules, and inducing the overexpression of gene products that contribute to drug resistance. Hypoxia-induced challenges described in this review are not limited to microtubule-stabilizing drugs alone, but in many cases also impact on treatment with non-microtubule-targeting anticancer drugs.