Novel insights into taxane pharmacology: An update on drug resistance mechanisms, immunomodulation and drug delivery strategies

Abstract

Taxanes are effective in several solid tumors. Paclitaxel, the main clinically available taxane, was approved in the early nineties, for the treatment of ovarian cancer and later on, together with the analogs docetaxel and cabazitaxel, for other malignancies. By interfering with microtubule function and impairing the separation of sister cells at mitosis, taxanes act as antimitotic agents, thereby counteracting the high proliferation rate of cancer cells. The action of taxanes goes beyond their antimitotic function because their main cellular targets, the microtubules, participate in multiple processes such as intracellular transport and cell shape maintenance. The clinical efficacy of taxanes is limited by the development of multiple resistance mechanisms. Among these, extracellular vesicles have emerged as new players. In addition, taxane metronomic schedules shows an impact on the tumor microenvironment reflected by antiangiogenic and immunomodulatory effects, an aspect of growing interest considering their inclusion in treatment regimens with immunotherapeutics. Preclinical studies have paved the bases for synergistic combinations of taxanes both with conventional and targeted agents. A variety of drug delivery strategies have provided novel opportunities to increase the drug activity. The ability of taxanes to orchestrate different cellular effects amenable to modulation suggests novel options to improve cures in lethal malignancies.

Keywords: Drug combination; Drug delivery; Drug resistance; Immunomodulation; Paclitaxel; Taxanes.