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Microtubule Damaging Agents and Apoptosis

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The Role of Microtubules in Cell Biology, Neurobiology, and Oncology

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Nowadays, molecules that affect microtubule functions, the so-called Microtubule-Damaging Agents (MDAs), constitute a class of anti-cancer drugs largely used in the clinics. Interest for MDAs is accompanied with advances in the fundamental understanding of their mechanism of action, including tumor cell death induction. MDAs have shown a high ability to induce apoptosis, programmed and tightly regulated cell death that is not or insufficiently activated in cancer cells. Here, the major intracellular signaling cascades responsible for apoptosis are first reviewed, focusing on the mitochondrial pathway. Then, the molecular and cellular mechanisms involved in the pro-apoptotic activity of MDAs are precised. Especially, the modulation of Bcl-2 family members that triggers mitochondrial membrane permeabilization is described, as well as the release of pro-apoptotic factors from the intermembrane space, and the final activation of caspases that leads to the biochemical destruction of the cell. Since MDAs inhibit microtubule functions and generally perturbate cell cycle progression, microtubule-linked proteins and cell-cycle progression regulators are proposed as candidates to control the apoptotic machinery. Other factors, such as MAPKs, stress markers, and survival factors, are also reviewed as modulators of the cell survival/death balance. Lastly, the direct effects of MDAs on mitochondria and the possible involvement of the tubulin/microtubule system in this phenomenon are discussed. Altogether, these data highlight the crucial role played by mitochondria in MDA-induced apoptosis, and propose that mitochondria should be investigated as a target of choice to improve cancer therapy.

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Authors and Affiliations

  1. UMR-Centre National de la Recherche Scientifique 2737, Faculté de Pharmacie, Université de la Méditerranée, Marseille, France

    Manon Carré

  2. Formation de Recherche en Evolution-Centre National de la Recherche Scientifique 2737, Faculté de Pharmacie, Université de la Méditerranée, Marseille, France

    Diane Braguer PhD

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  1. Manon Carré
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  1. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD

    Tito Fojo MD, PhD

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Carré, M., Braguer, D. (2008). Microtubule Damaging Agents and Apoptosis. In: Fojo, T. (eds) The Role of Microtubules in Cell Biology, Neurobiology, and Oncology. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-336-3_18

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