Review Article Emphasizes the Multifold Effect of Taxanes on Prostate Cancer Cells

Docetaxel is a synthetic derivative of paclitaxel, and like paclitaxel, promotes the formation of microtubules that do not function properly. One of the roles of normal microtubules is to aid in cell duplication, and by disrupting this function, docetaxel inhibits cell reproduction.

However, this class of drug can have debilitating side effects including permanent neurological damage and hair loss.

Recent studies have shown that paclitaxel, which is commonly used for the treatment of prostate cancer, inhibited signaling from the androgen receptor by inhibiting its nuclear accumulation downstream of microtubule stabilization. This mechanism was independent of paclitaxel-induced mitotic arrest and could provide an alternative mechanism of drug action that could explain its clinical activity.

In a review published in the September 15, 2012, issue of the journal Cancer Research, investigators at Weill Cornell Medical College (New York, NY, USA) highlighted the importance of signaling and trafficking pathways that depend on intact and dynamic microtubules, which represent downstream targets of microtubule inhibitors. They showcased prostate cancer, which is driven by the activity of the androgen receptor, as recent reports have revealed a connection between the microtubule-dependent trafficking of the androgen receptor and the clinical efficacy of taxanes.

"Taxanes are one of the best class of chemotherapy drugs that we can use to treat our cancer patients, but while they are effective against a wide range of tumors, they do not work in all of them, and often patients become resistant," said senior author Dr. Paraskevi Giannakakou, associate professor of pharmacology at Weill Cornell Medical College. "In the 20 years since Taxol was approved, hundreds of labs worldwide are trying to understand how taxanes work to stop cell division in cancer. "However, we think they need to now take a fresh approach and look at what these drugs do during the normal life cycle of a cancer cell and target the newly revealed underlying mechanisms and modes of movement with novel therapies, in combination with taxane therapy, to provide life-saving therapy for patients who do not benefit from taxanes."

"Microtubules are the highly dynamic network of wires within cells, and when taxanes are used, the network stops moving," said Dr. Giannakakou. "This is best observed when cancer cells attempt to divide. It is easy to see in the laboratory, that prostate cancer cells double every 30-48 hours, and taxane stops them from doing that, which pushes these cells to die. This leads everyone to think that this is exclusively how taxanes work – they stop cells from dividing. In fact, cancer cells in prostate cancer patients only divide every 33-577 days. Thus, the therapeutic benefit of taxanes on microtubules depends on more than just stopping cell division."

Identification and further elucidation of microtubule-dependent tumor-specific pathways will help researchers to better understand the molecular basis of clinical taxane resistance as well as to identify individual patients more likely to respond to treatment.

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