Hydroxyl radicals mediates cisplatin-induced apoptosis in human hair follicles dermal papilla cells and keratinocytes through Bcl-2-dependent mechanism.
Luanpitpong-S; Chanvorachote-P; Pongrakhananon-V; Wang-L; Nimmannit-U; Rojanasakul-Y
Toxicologist 2011 Mar; 120(Suppl 2):359
Induction of massive apoptosis of hair follicle cells by chemotherapy has been implicated in the pathogenesis of chemotherapy-induced alopecia (CIA), but the underlying mechanisms of regulation are not well understood. The present study investigated the apoptotic effect of cisplatin in human hair follicle dermal papilla cells (HFDPC) and HaCaT keratinocytes, and determined the role of reactive oxygen species (ROS) in the process. Treatment of the cells with cisplatin induced ROS generation and a parallel increase in caspase activation and apoptotic cell death in HFDPC and HaCaT cells. Inhibition of ROS generation by antioxidants, N-acetyl cysteine and reduced glutathione, inhibited the apoptotic effect of cisplatin, indicating the role of ROS in the process. Studies using specific ROS scavengers further showed that hydroxyl radical, but not hydrogen peroxide or superoxide anion, is the primary oxidative species responsible for the apoptotic effect of cisplatin. The mechanism by which hydroxyl radical mediates the effect of cisplatin was shown to involve down-regulation of anti-apoptotic protein Bcl-2 through ubiquitin-proteasomal degradation. Bcl-2 was also shown to have a negative regulatory role on hydroxyl radical. Together, our results indicate an essential role of hydroxyl radical in cisplatin-induced cell death of hair follicle cells through Bcl-2 regulation. Since CIA is a major side effect of cisplatin and many other chemotherapeutic agents with no known effective treatments, the knowledge gained from this study could be useful in the design of preventive treatment strategies for CIA through localized therapy without negatively affecting the chemotherapy efficacy.
Biological-effects; Cell-biology; Cell-function; Cell-metabolism; Cell-morphology; Cellular-reactions; Chemotherapy; Microscopic-analysis; Microscopy; Oxidative-metabolism; Oxidative-processes; Physiological-effects; Quantitative-analysis
The Toxicologist. Society of Toxicology 50th Annual Meeting and ToxExpo, March 6-10, 2011, Washington, DC