Discovery Of Taxol Mechanism Could Help Develop Better Cancer Drugs
Researchers from the University of California, Berkeley reported the discovery of a highly subtle effect of the prescription drug Taxol on cell microtubules. The discovery could lead to the development of improved anticancer treatments.
Taxol is originally derived from the bark of the Pacific yew tree and is one of the most widely used drugs against solid tumors. The drug is a front-line treatment against ovarian and advanced breast cancer. Taxol binds to microtubules and freezes them in place to prevent them from separating the chromosomes when cells divide. The mechanism is particularly effective against cancer cells, which often grow rapidly.
Nogales and her team discovered that Taxol inserts itself into the tubulin protein and keeps the alpha and beta subunits from compacting. This results in the lack of tension that triggers the separation of the tubulins. The drug’s mechanism keeps the microtubules intact and frozen, unable to depolymerize and carry out normal functions, including proliferation.
“Efforts towards understanding these chemotherapeutics better are very important, because there are some microtubule differences in cancer cells versus normal cells that maybe we can exploit. We are not there yet, but this is the kind of analysis we need to get there,” said principal author Eva Nogales, biophysicist and UC Berkeley professor of molecular and cell biology and senior faculty scientist at Lawrence Berkeley National Laboratory (LBNL).
The team used an advanced cryoelectron microscopy technique in which samples are frozen and analyzed with a high powered electron beam. Nogales was able to examine 3D microtubules frozen in their natural state, with and without Taxol acting on its tubulin. The comparison clearly demonstrated the drug’s mechanism of action on the cell’s structure.
The researchers’ findings appear in the journal Cell. “This work represents a major step forward on a problem with a long history,” wrote Tim Mitchison, a Harvard University professor of systems biology, in a commentary in the same issue of Cell. Mitchison added that the model proposed by the researchers affords a breakthrough glimpse into destabilization mechanism of Taxol on cancer cells.