Clearance of Senescent Cells Reverses Cisplatin-induced Peripheral Neuropathy in Mice

Abstract

Radiation and chemotherapy-induced neuropathy represent some of the most common causes of dose reduction and discontinuation of cancer treatment, often leaving patients with major permanent impairment of quality of life. Moreover, chemotherapy-induced neuropathy acts as a risk factor for development of radiation-induced neuropathy in patients receiving concomitant or adjuvant radiation therapy. The lack of effective treatments for or prevention of this debilitating neuronal toxicity not only compromises optimal treatment, but also leaves cancer survivors with significant disability. Here, we sought to investigate the biological role of senescence in cisplatin neurotoxicity and to evaluate the efficacy of pharmacological clearance of senescent cells. A murine model was established to measure the development of cisplatin-induced peripheral neuropathy (CIPN) in wild-type mice. The hyperalgesia seen in neuropathy was measured in terms of mechanical and thermal thresholds. SA-β-gal staining, p16 expression, and Mmp-9 mRNA expression were used to monitor senescence in primary cultured dorsal root ganglion (DRG) neurons. The effect of senescent cell clearance by the senolytic agent ABT-263 was examined using wild-type mice in the neuropathy model. Finally, using transgenic p16-3MR mice that allow for tracking and elimination of senescent cells by ganciclovir (GCV), we verified the efficacy of senescent cell clearance by ABT-263. CIPN was induced and measured in mice, showing consistent reduction in thermal and mechanical tolerance. Cisplatin provoked a significant increase in senescence in primary cultured DRG neurons as demonstrated by increased SA-β-gal positive cells, p16 expression, and Mmp-9 mRNA expression. Clearance of senescent cells using ABT-263 abolished CIPN in wild-type mice as evidenced by reversal of decreased mechanical and thermal thresholds to pre-cisplatin levels. Lastly, ABT-263 inhibition of senescence showed equally effective treatment of CIPN compared to GCV-mediated clearance of senescent cells in p16-3MR mice. ABT-263 treatment reverses cisplatin-induced peripheral neuropathy through clearance of senescent cells. Identification of this novel function warrants future investigation of senolytic-mediated reversal of neurotoxicity following platinum-based cancer treatment.