Study Identifies Molecular Basis of Pain Caused by Cancer Drug

New Haven, Conn. — Peripheral pain, a side effect of the highly effective cancer drug paclitaxel, appears to be caused when the drug binds to a protein and initiates improper calcium signaling, a Yale School of Medicine researcher reports in a study published recently in the Proceedings of the National Academy of Sciences.

“This response leads to the generation of side effects such as acute hypersensitivity, slower heart rhythms, tingling, numbness, and other symptoms,” said Barbara Ehrlich, professor of pharmacology and physiology and lead author of the study.

Paclitaxel, a substance isolated from the pacific yew Taxus brevifolia and approved by the FDA in 1990, has been very successful in treating solid tumors such as breast cancer and ovarian cancer. However, serious side effects limit its effectiveness. Peripheral pain, for instance, becomes worse with continued use of paclitaxel and increased dosages lead to persistent and irreversible pain, Ehrlich said.


Neurons isolated from a rat stained to show the distribution of calcium signaling molecules -- green is the channel that lets calcium out of the storage location (the endoplasmic reticulum), blue is the nucleus, red is fibroblasts (not affected by drug).
For this study her team used paclitaxel in the normal therapeutic range. Ehrlich said previous studies of paclitaxel-induced peripheral pain were based on concentrations 10 times higher than those given to patients.

What the researchers found is a new binding protein for paclitaxel—neuronal calcium sensor-1 (NCS-1). When paclitaxel binds to NCS-1, it makes the cell more sensitive to normal signals and increases the magnitude and frequency of changes in calcium. Over time, increased calcium levels activate an enzyme, calpain, that degrades proteins, especially NCS-1.

Calcium signals are needed for nerves to be stimulated and to respond, and the loss of NCS-1 makes it more difficult to generate any calcium signals, she said. While the loss of NCS-1 stops the protein interaction that is causing the inappropriate calcium signals, it also decreases the ability to have normal responses.

Ehrlich said the findings will be of interest to basic scientists and clinical investigators since paclitaxel is widely used to treat solid tumors.

“Our results will be an important contribution towards the development of more effective cancer therapies with fewer side effects,” she said.