Paclitaxel and cancer treatment: Non-mitotic mechanisms of paclitaxel action in cancer therapy

Paclitaxel (trade name Taxol) is a key drug used in chemotherapy for many solid tumors including ovarian, breast, lung, and prostate cancer. In the current treatment of ovarian cancer, paclitaxel is used as a frontline agent in combination with cisplatin (or carboplatin), and as a second line drug with a dose intensive regimen following recurrence. The molecular target of paclitaxel has been identified as tubulin, and paclitaxel (and other microtubule-stabilizing agents) alters the dynamics of and stabilizes microtubule filaments. Traditionally the anti-cancer mechanism asserts that paclitaxel interferes with the function of microtubules in mitosis, resulting in mitotic arrest followed by apoptosis. Paclitaxel also kills cancer cells by inducing aberrant multipolar division and interfering with microtubule-dependent cellular transport and signaling. However, recent evidence suggests that additional, non-mitotic mechanisms targeting microtubules may be more important than inhibiting mitosis for the success of paclitaxel as an anti-cancer drug. The formation of multiple micronuclei appears to be an important aspect of paclitaxel in the killing of cancer cells. A unique pharmacokinetic property of paclitaxel is that the compound is sequestered and concentrated within cells, and paclitaxel activity persists for several days following drug administration/infusion. The retention of paclitaxel within cells likely is a factor contributing to the efficacy of the drug, but also accounts for side effects such as peripheral neuropathy and alopecia. The current review discusses the potential mechanisms of paclitaxel action, particularly the formation of multiple micronuclei and the triggering of innate immunity and the bystander effect. Based on the knowledge of the mechanisms by which paclitaxel kills cells, we also discuss concepts, laboratory experimental observations, and clinical trials in effort to combine paclitaxel with other agents such as FTI (Farnesyl Transferase Inhibitor), CDK4/6 inhibitor, and immune modulators, in the treatment of cancer.