Breaking malignant nuclei as a non-mitotic mechanism of taxol/paclitaxel.

Abstract

Discovered in a large-scale screening of natural plant chemicals, Taxol/paclitaxel and the taxane family of compounds are surprisingly successful anti-cancer drugs, used in treatment of the majority of solid tumors, and especially suitable for metastatic and recurrent cancer. Paclitaxel is often used in combination with platinum agents and is administrated in a dose dense regimen to treat recurrent cancer. The enthusiasm and clinical development were prompted by the discovery that Taxol binds beta-tubulins specifically found within microtubules and stabilizes the filaments, and consequently inhibits mitosis. However, questions on how paclitaxel suppresses cancer persist, as other specific mitotic inhibitors are impressive in pre-clinical studies but fail to achieve significant clinical activity. Thus, additional mechanisms, such as promoting mitotic catastrophe and impacting non-mitotic targets, have been proposed and studied. A good understanding of how paclitaxel, and additional new microtubule stabilizing agents, kill cancer cells will advance the clinical application of these common chemotherapeutic agents. A recent study provides a potential non-mitotic mechanism of paclitaxel action, that paclitaxel-induced rigid microtubules act to break malleable cancer nuclei into multiple micronuclei. Previous studies have established that cancer cells have a less sturdy, more pliable nuclear envelope due to the loss or reduction of lamin A/C proteins. Such changes in nuclear structure provide a selectivity for paclitaxel to break the nuclear membrane and kill cancer cells over non-neoplastic cells that have a sturdier nuclear envelope. The formation of multiple micronuclei appears to be an important aspect of paclitaxel in the killing of cancer cells, either by a mitotic or non-mitotic mechanism. Additionally, by binding to microtubule, paclitaxel is readily sequestered and concentrated within cells. This unique pharmacokinetic property allows the impact of paclitaxel on cells to persist for several days, even though the circulating drug level is much reduced following drug administration/infusion. The retention of paclitaxel within cells likely is another factor contributing to the efficacy of the drugs. Overall, the new understanding of Taxol/paclitaxel killing mechanism-rigid microtubule-induced multiple micronucleation-will likely provide new strategies to overcome drug resistance and for rational drug combination.