How Taxol/paclitaxel kills cancer cells

Abstract

Taxol (generic name paclitaxel) is a microtubule-stabilizing drug that is approved by the Food and Drug Administration for the treatment of ovarian, breast, and lung cancer, as well as Kaposi's sarcoma. It is used off-label to treat gastroesophageal, endometrial, cervical, prostate, and head and neck cancers, in addition to sarcoma, lymphoma, and leukemia. Paclitaxel has long been recognized to induce mitotic arrest, which leads to cell death in a subset of the arrested population. However, recent evidence demonstrates that intratumoral concentrations of paclitaxel are too low to cause mitotic arrest and result in multipolar divisions instead. It is hoped that this insight can now be used to develop a biomarker to identify the ∼50% of patients that will benefit from paclitaxel therapy. Here I discuss the history of paclitaxel and our recently evolved understanding of its mechanism of action.

FIGURE 1:

Clinically relevant concentrations of paclitaxel kill tumor cells by inducing multipolar divisions. Cells entering mitosis in the presence of concentrations of paclitaxel equivalent to those in human breast tumors form abnormal spindles that contain additional spindle poles. Rather than mounting a long-term mitotic arrest, these cells enter anaphase and divide their chromosomes in multiple directions. However, a portion of the cytokinetic furrows often fail, and two or three daughter cells are usually produced. Chromosome segregation is randomized due to multipolar division followed by partial cytokinesis failure. The resultant daughter cells are aneuploid, and a portion of these die (red X), presumably due to loss of one or more essential chromosomes.