Abstract
Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16INK4A and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological ‘senolytic’ agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN.
Highlights
Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients
We showed that cisplatin induces peripheral neuropathy, as confirmed by mechanical and thermal pain assessment, and was associated with the accumulation of senescent-like neuronal cells in the dorsal root ganglia (DRG) using immunostaining and Quantitative PCR (qPCR) for senescence biomarkers
To determine whether senescent cells play a role in cisplatin-induced peripheral neuropathy (CIPN), we first investigated whether cisplatin induces a senescence-like state in DRG by localizing and measuring biomarkers for senescent cells in cultured primary DRG neurons following cisplatin treatment
Summary
Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. The results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN. Cisplatin’s antineoplastic effects are achieved through the formation of platination products in nuclear DNA7–9 These DNA-base crosslinks distort DNA helices, interrupting replication and transcription, eventually inducing cell cycle arrest, senescence, or cell d eath[7,8,9,10].While these effects of cisplatin on cancer cells is desired for treatment, the same processes in normal tissue can cause toxicity. Despite the relatively low proportion of senescent cells in tissues, the SASP allows these cells to generate durable local and systemic deleterious effects in most tissues, which contribute to the pathogenesis of a variety of diseases including chemotherapy toxicity[11]
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