The power of taxane-based chemotherapy drugs are misunderstood and potentially underestimated, according to researchers at Weill Cornell Medical College in the September 15 issue of the journal Cancer Research.
Most physicians and investigators believe that taxane chemotherapy (paclitaxel, docetaxel and cabazitaxel) just does one thing -- stop a cancer cell from dividing -- but the team of Weill Cornell scientists have revealed it acts much more powerfully and broadly, especially against prostate cancer.
"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 don't work in all of them, and often patients become resistant," says the study's senior investigator, Dr. Paraskevi Giannakakou, an associate professor of pharmacology in medicine and pharmacology and director of laboratory research for the Division of Hematology and Medical Oncology at Weill Cornell. "However, our new understanding of the precise action of taxanes in a cancer cell may help us overcome drug insensitivity or acquired resistance to the drugs and design therapies that can be used in combination with them to improve cancer control."
In their study, the researchers stress that investigators must shift their attention away from taxane's function during cell division to the drugs' effects on halting the everyday movement of proteins and protein-to-protein communication within cancer cells -- and to understanding how and why a cancer cell can still survive. Researchers suggest that cancers that are insensitive to taxanes -- or those that have become resistant to them -- may, for example, switch to alternate forms of "transportation" to shuttle proteins within cells in a way that does not depend on the cell's skeletal structure which is the target of taxane therapy.
Researchers showed in the study that the androgen receptor (AR), which is a driving force in prostate cancer growth and metastasis, "moves" along microtubules to be transported to the nucleus. When a taxane binds microtubules, it stops AR from traveling, thus inhibiting its activity. Taxane chemotherapy drugs such as paclitaxel, docetaxel and cabazitaxel work by binding tubulin, a protein that makes up microtubules. Microtubules are the rope-like channels that provide both a skeletal structure to cells as well as provide "highways" along which molecules, such as proteins, RNA complexes and vesicles, can travel from one part of the cell to another and interact with each other.
"Microtubules are the highly dynamic network of wires within cells, and when taxanes are used, the network stops moving," says Dr. Giannakakou. This is best observed when cancer cells attempt to divide, she says. "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."