Therapy-Induced Senescence (TIS) is a form of senescence that is typically described in malignant cells in response to the exposure of cancer chemotherapy or radiation but can also be precipitated in non-malignant cells. TIS has been shown to contribute to the development of several cancer therapy–related adverse effects; however, evidence on its role in mediating chemotherapy-induced neurotoxicity, such as Chemotherapy-induced Peripheral Neuropathy (CIPN), is limited. We here show that cisplatin treatment over two cycles (cumulative dose of 23 mg/kg) provoked mechanical allodynia and thermal hyperalgesia in Sprague–Dawley rats. Isolation of dorsal root ganglia (DRG) from the cisplatin-treated rats demonstrated robust SA-β-gal upregulation at both day 8 (after the first cycle) and day 18 (after the second cycle), decreased lmnb1 expression, increased expression of cdkn1a and cdkn2a, and of several factors of the Senescence-associated Secretory Phenotype (SASP) (Il6, Il1b, and mmp9). Moreover, single-cell calcium imaging of cultured DRGs revealed a significant increase in terms of the magnitude of KCl-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats. No significant change was observed in terms of the magnitude of capsaicin-evoked calcium responses in cisplatin-treated rats compared to vehicle-treated rats but with decreased area under the curve of the responses in cisplatin-treated rats. Further evidence to support the contribution of TIS to therapy adverse effects is required but should encourage the use of senescence-modulating agents (senotherapeutics) as novel palliative approaches to mitigate chemotherapy-induced neurotoxicity.

治疗诱导衰老 (TIS) 是衰老的一种形式，通常在恶性细胞中描述为对癌症化疗或放疗的反应，但也可以在非恶性细胞中沉淀。TIS 已被证明会导致多种癌症治疗相关不良反应的发生；然而，关于其在介导化疗引起的神经毒性（例如化疗引起的周围神经病变（CIPN））中的作用的证据有限。我们在此表明​​，两个周期的顺铂治疗（累积剂量为 23 mg/kg）会引起 Sprague-Dawley 大鼠的机械异常性疼痛和热痛觉过敏。从顺铂治疗的大鼠中分离出背根神经节 (DRG)，结果表明 SA-β-gal 在第 8 天（第一个周期后）和第 18 天（第二个周期后）均出现强烈上调，lmnb1表达减少， cdkn1a表达增加和cdkn2a，以及衰老相关分泌表型 (SASP) 的几个因素（Il6、Il1b和mmp9）。此外，培养的 DRG 的单细胞钙成像显示，与媒介物治疗的大鼠相比，顺铂治疗的大鼠中 KCl 引起的钙反应的幅度显着增加。与媒介物治疗的大鼠相比，在顺铂治疗的大鼠中辣椒素诱发的钙反应的幅度没有观察到显着变化，但顺铂治疗的大鼠中反应曲线下面积减小。需要进一步的证据来支持 TIS 对治疗不良反应的贡献，但应鼓励使用衰老调节剂（senotherapeutics）作为减轻化疗引起的神经毒性的新姑息方法。