Paclitaxel Through the Ages of Anticancer Therapy: Exploring Its Role in Chemoresistance and Radiation Therapy

Abstract

Paclitaxel (Taxol(®)) is a member of the taxane class of anticancer drugs and one of the most common chemotherapeutic agents used against many forms of cancer. Paclitaxel is a microtubule-stabilizer that selectively arrests cells in the G2/M phase of the cell cycle, and found to induce cytotoxicity in a time and concentration-dependent manner. Paclitaxel has been embedded in novel drug formulations, including albumin and polymeric micelle nanoparticles, and applied to many anticancer treatment regimens due to its mechanism of action and radiation sensitizing effects. Though paclitaxel is a major anticancer drug which has been used for many years in clinical treatments, its therapeutic efficacy can be limited by common encumbrances faced by anticancer drugs. These encumbrances include toxicities, de novo refraction, and acquired multidrug resistance (MDR). This article will give a current and comprehensive review of paclitaxel, beginning with its unique history and pharmacology, explore its mechanisms of drug resistance and influence in combination with radiation therapy, while highlighting current treatment regimens, formulations, and new discoveries.

Keywords: cancer; chemoradiotherapy; chemotherapy; multidrug resistance; paclitaxel.

Figure 1

Chemical structure of paclitaxel.

Figure 2

The Major Mechanisms of Paclitaxel Resistance. The cellular mechanism of action by which paclitaxel serves as an anticancer drug, as illustrated following the black arrows. Paclitaxel enters the cell and binds to b-tubulin on the inner surface of microtubules. This stabilizes the microtubule network, arrests the cell cycle at the G2/M phase, and therefore leads to apoptosis. Cancer cells have been found to evade the microtubule stabilizing action of paclitaxel through three main mechanisms (illustrated in red): (1) over-expression of transmembrane efflux transporters, specifically ABCB1 and ABCC10; (2) tubulin mutations (both α and β) or alterations in the stability of the microtubule network; and (3) reduced function of significant apoptotic proteins, such as Bcl-2 and p53.