Editing Microtubule (section)

===Tubulin-binding drugs and chemical effects===

A wide variety of [[drug]]s are able to bind to tubulin and modify its assembly properties.  These drugs can have an effect at intracellular concentrations much lower than that of tubulin. This interference with microtubule dynamics can have the effect of stopping a cell's [[cell cycle]] and can lead to [[programmed cell death]] or [[apoptosis]]. However, there are data to suggest that interference of microtubule dynamics is insufficient to block the cells undergoing mitosis.<ref>{{Cite journal |vauthors=Ganguly A, Yang H, Cabral F |date=November 2010 |title=Paclitaxel-dependent cell lines reveal a novel drug activity |journal=Molecular Cancer Therapeutics |volume=9 |issue=11 |pages=2914–23 |doi=10.1158/1535-7163.MCT-10-0552 |pmc=2978777 |pmid=20978163}}</ref> These studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. Suppression of microtubule dynamics by tubulin mutations or by drug treatment have been shown to inhibit cell migration.<ref name="pmid20696757">{{Cite journal |vauthors=Yang H, Ganguly A, Cabral F |date=October 2010 |title=Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs |journal=The Journal of Biological Chemistry |volume=285 |issue=42 |pages=32242–50 |doi=10.1074/jbc.M110.160820 |pmc=2952225 |pmid=20696757 |doi-access=free}}</ref>  Both microtubule stabilizers and  destabilizers can suppress microtubule dynamics.

The drugs that can alter microtubule dynamics include:
* The cancer-fighting [[taxane]] class of drugs ([[paclitaxel]] (taxol) and [[docetaxel]]) block dynamic instability by stabilizing GDP-bound tubulin in the microtubule. Thus, even when hydrolysis of GTP reaches the tip of the microtubule, there is no depolymerization and the microtubule does not shrink back.
Taxanes (alone or in combination with platinum derivatives (carboplatine) or gemcitabine) are used against breast and gynecological  malignancies, squamous-cell carcinomas (head-and-neck cancers, some lung cancers), etc.
* The [[epothilone]]s, e.g. [[Ixabepilone]], work in a similar way to the taxanes.
* Vinorelbine, [[Nocodazole]], [[vincristine]], and [[colchicine]] have the opposite effect, blocking the polymerization of tubulin into microtubules.
* [[Eribulin]] binds to the (+) growing end of the microtubules. Eribulin exerts its anticancer effects by triggering apoptosis of cancer cells following prolonged and irreversible mitotic blockade.

Expression of β3-tubulin  has been reported to alter cellular responses to drug-induced suppression of microtubule dynamics. In general  the dynamics are normally suppressed by low, subtoxic concentrations of microtubule drugs that also inhibit cell migration. However, incorporating β3-tubulin into microtubules increases the concentration of drug that is needed to suppress dynamics and inhibit cell migration. Thus, tumors that express β3-tubulin are not only resistant to the cytotoxic effects of microtubule targeted drugs, but also to their ability to suppress tumor metastasis.<ref>{{Cite journal |last1=Altonsy |first1=Mohammed |last2=Ganguly |first2=Anutosh |last3=Amrein |first3=Matthias |last4=Surmanowicz |first4=Philip |last5=Li |first5=Shu |last6=Lauzon |first6=Gilles |date=Mar 2020 |title=Beta3-Tubulin Is Critical for Microtubule Dynamics, Cell Cycle Regulation, and Spontaneous Release of Microvesicles in Human Malignant Melanoma Cells (A375) |journal=International Journal of Molecular Sciences |volume=21 |issue=5 |page=1656 |doi=10.3390/ijms21051656 |pmc=7084453 |pmid=32121295 |doi-access=free}}</ref> Moreover, expression of β3-tubulin also counteracts the ability of these drugs to inhibit angiogenesis which is normally another important facet of their action.<ref>{{Cite journal |last1=Ganguly |first1=Anutosh |last2=Yang |first2=Hailing |last3=Fernando |first3=Gabral |date=May 2011 |title=Class III β-Tubulin Counteracts the Ability of Paclitaxel to Inhibit Cell Migration |journal=Oncotarget |volume=2 |issue=5 |pages=368–377 |doi=10.18632/oncotarget.250 |pmc=3248193 |pmid=21576762}}</ref>

Microtubule polymers are extremely sensitive to various environmental effects. Very low levels of free calcium can destabilize microtubules and this prevented early researchers from studying the polymer in vitro.<ref name="weisenberg" /> Cold temperatures also cause rapid depolymerization of microtubules. In contrast, [[heavy water]] promotes microtubule polymer stability.<ref>{{Cite journal |vauthors=Burgess J, Northcote DH |date=September 1969 |title=Action of colchicine and heavy water on the polymerization of microtubules in wheat root meristem |journal=Journal of Cell Science |volume=5 |issue=2 |pages=433–51 |doi=10.1242/jcs.5.2.433 |pmid=5362335}}</ref>