Submitted by Shan (Sarah) Chen, MD, PhD, News Science Editorial Board
Edited by Nandita S. Keole, MD, News Science Editorial Board
Pease-Raissi SE, Pazyra-Murphy MF, Li Y, Wachter F, Fukuda Y, Fenstermacher SJ, Barclay LA, Bird GH, Walensky LD, Segal RA. (2017). Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration. Neuron. 96. 373-386.e6. 10.1016/j.neuron.2017.09.034.
Chemotherapeutic agents that cause chemotherapy-induced peripheral neuropathy (CIPN) include platinum drugs, vinca alkaloids, and taxanes such as Paclitaxel. Paclitaxel is a microtubule stabilizing agent often used to treat patients with breast, ovarian, lung, or other cancer, and causes a primarily sensory polyneuropathy. In patients with CIPN, degeneration of long peripheral sensory or motor neuron axons causes pain, numbness, tingling, and/or muscle weakness. Currently, there are no disease-modifying therapies available besides pain medications. The molecular mechanisms of chemotherapy-induced axonal degeneration are unclear.
This excellent study by Dr. Segal’s laboratory demonstrated that one of the commonly used chemotherapeutic agents, Paclitaxel, triggers CIPN by altering IP3 receptor (IP3R1) phosphorylation and reducing synthesis of Bclw (a Bcl2 family member).
Comments: According to this article, Bclw serves as a deterrent on the IP3R1-dependent axonal degeneration cascade by inhibiting the pro-degenerative effects of IP3R1 activity. Paclitaxel, by attenuating axonal transport and translation of bclw in axons, reduces axonal Bclw levels or even depletes Bclw store and thus removes the brakes on the cascade, resulting in axonal degeneration, and clinically manifests as CIPN. This model also suggests that Bclw-mimics could provide effective therapy to prevent CIPN.