Confocal Microscopy and Live Cell Imaging
Molecular Basis of Microtubule Drug Resistance
The gravity of the drug resistance problem in clinical oncology has led to intense scientific efforts to understand the molecular mechanisms that lead to drug resistance, as well as to identify the ways to overcome it. In the case of Taxol, several mechanisms of resistance have been described. With the exception of P-glycoprotein (Pgp)-mediated multi-drug resistance (MDR) resulting in decreased intracellular drug accumulation, all other mechanisms appear to involve alterations in tubulin. Such alterations include: 1) differential expression levels of β-tubulin isotypes in Taxol-resistant cells; 2) an increase in microtubule dynamics in Taxol-resistant cancer cells, as well as decreased ability of Taxol to suppress microtubule dynamics in cells overexpressing βIII-tubuling. Our laboratory was the first to describe the presence of tubulin mutations as found in Taxol-resistant cell lines. (P. Giannakakou, D.L. Sackett, et.al. Journal of Biological Chemistry, 1997, 272(27):17118-17125.) (P. Giannakakou, R. Gussio, et.al. Proc. Natl. Acad. Sci. USA, 2000, 97(6):2904-2909.)
Since then, several other groups have described acquired tubulin mutations in human cancer cells lines which confer resistance to either microtubule-stabilizing or microtubule-destabilizing drugs, making tubulin mutations one of the most frequently encountered mechanisms of antitubulin drug resistance. In the end, what this means is that no matter where an organism is on the phylogenetic tree, it may be capable of acquiring mutations in its tubulin genes as a mechanism that allows these organisms to survive in otherwise toxic circumstances, such as in the presence of the powerful tubulin-targeting drugs. Thus, the acquisition of mutations that alter cellular microtubules' response to drug binding appears to be a simple but universal mechanism for an organism's survival in the presence of these drugs.
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