Deciphering the molecular mechanisms of anti-tubulin plant derived drugs

Abstract

International audienceEven though commercialized anticancer drugs are now produced by pharmaceutical companies, most of them were originally obtained from natural sources, and more particularly from plants. Indeed, many structurally diverse compounds isolated from plants or marine flora have been purified and synthesized for their anticancer bioactivity. Among these, several molecules belong to the class of anticancer drugs which target the microtubule cytoskeleton, either by stabilizing it or destabilizing it. To characterize the activity of these drugs and to understand in which physiological context they are more likely to be used as therapeutic agents, it is necessary to fully determine their interaction with tubulin. Understanding the molecular basis of their effects on microtubule cytoskeleton is an important step in designing analogs with greater pharmacological activity and with fewer side effects. In addition, knowing the molecular mechanism of action of each drug that is already used in chemotherapy protocols will also help to find strategies to circumvent resistance. By taking examples of known anti-tubulin plant derived drugs, we show how identification of microtubule targeting agents and further characterization of their activity can be achieved combining biophysical and biochemical approaches. We also illustrate how continuing in depth study of molecules with already known primary mechanisms of action can lead to the discovery of new targets or biomarkers which can open newperspectives in anticancer strategies

Stiffening of prostate cancer cells driven by actin filaments – microtubules crosstalk confers resistance to microtubule-targeting drugs

“…Microtubule stabilizing and destabilizing drugs disrupt microtubule functioning, which is accomplished by various mechanisms. Vinca alkaloids destabilize microtubules by binding to a site located at the inter-dimeric interface between  and β tubulin heterodimers 15 . They induce the formation of alternate microtubules leading to the dissociation of existing microtubules 38,39 .…”

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth

“…We will briefly mention these assays here. For more detailed information, we refer to the review of Barbier et al 29 on the molecular mechanisms of antitubulin plant-derived drugs.…”

Characterization of Microtubule-Associated Proteins (MAPs) and Tubulin Interactions by Isothermal Titration Calorimetry (ITC)

“…In this context, MTA binding to tubulin has also been extensively studied using a wide variety of methods [12]. Characterizing this interaction is an essential step to test whether a suspected novel anticancer agent is an MTA [13][14][15].…”

“…It was first used to give a full thermodynamics characterization of stathmin-tubulin interaction [16] and later to describe the impact of the phosphorylation of the four individual serine residues of stathmin on its structure and on its interaction with tubulin [17]. It was also used to show by which molecular mechanism overexpression of stathmin could potentiate the anticancer activity of vinca alkaloids and decrease the activity of taxanes [13][14][15] opening new perspectives to cancer therapies.…”