Microtubule-targeted agents: When mitochondria become essential to chemotherapy

Abstract

Microtubule-Targeting Agents (MTAs) constitute a class of drugs largely used for cancer treatment in adults and children. In cancer cells, they suppress microtubule dynamics, and induce cell death via the mitochondrial intrinsic pathway. To date, links between mitochondria and microtubule network disturbance in MTAs mechanism of action are not obvious. The aim of the present contribution is to provide elements that could answer to the question: how far are mitochondria essential to anticancer chemotherapy that targets the microtubule cytoskeleton? We review the main molecular candidates to link microtubule alteration with the apoptotic mitochondrial pathway control. Involvement of direct targeting of mitochondria in MTA efficacy is also discussed. Furthermore, we line up current evidence and emerging concepts on the participation of both mitochondria and microtubule in MTA neurotoxic side effects. To decipher the interconnections between the mitochondrial and the microtubule networks may help to improve cancer cell response to chemotherapy.

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins

“…Given the importance of MTs in cell division and the widely accepted concept that cancer cells divide more rapidly than normal cells, it has been generally assumed that MTAs mediate cytotoxicity by interfering with mitosis (1, 2). Elegant in vitro and preclinical data have demonstrated time and again that MTAs lead to mitotic arrest and in turn cell death (5,(7)(8)(9)(10)(11)(12). Arrest in mitosis as the mechanism that leads to cell death is possible in these preclinical models because their doubling times range from a few hours to at most a few days, and even brief drug exposures are likely to encounter a substantial fraction of cells traversing through mitosis.…”

Microtubules and Their Role in Cellular Stress in Cancer

“…There is growing evidence that tubulin, microtubules, and the microtubule network regulate mitochondrial function in cancer (217). Microtubules are involved in mitochondrial trafficking and degradation, with these processes influencing microtubule stability and tubulin degradation (218).…”

“…Microtubules are involved in mitochondrial trafficking and degradation, with these processes influencing microtubule stability and tubulin degradation (218). Tubulin is an integral component of mitochondrial membranes (136, 137, 219), and these membranes are enriched with βIII-tubulin (107, 137, 217). Mitochondria-associated βIII-tubulin is distinguished from the cytoplasmic tubulin pool by distinct post-translational modifications (107).…”

“…High Bcl-xL levels are protective against taxol-induced cell stress (225). These effects may be explained by direct interactions between Bcl-2 and tubulin (217, 227). Bcl-2 interacting mediator of cell death (Bim) is also sequestered on microtubules by binding to the dynein light chain, thereby preventing initiation of apoptotic signaling (227, 228).…”

ROS-mediated EB1 phosphorylation through Akt/GSK3β pathway: implication in cancer cell response to microtubule-targeting agents

“…It is well established that MTAs activate the intrinsic apoptotic pathway, and especially mitochondria membrane permeabilization and cytochrome c release [extensively reviewed in 10-11]. MTA anti-mitochondrial activities can result from a modulation of Bcl-2 family members' expression levels [12-14] or from a direct targeting of mitochondrial membranes [15-16].…”