Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan.
Department of Basic Dental Sciences, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan.
Neurotox Res. 2024 Jan 31;42(1):10. doi: 10.1007/s12640-024-00690-7.
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.
治疗诱导的衰老（TIS）是一种衰老形式，通常在恶性细胞中描述为对癌症化疗或辐射的暴露的反应，但也可以在非恶性细胞中引发。TIS 已被证明有助于几种癌症治疗相关不良反应的发展；然而，关于其在介导化疗诱导的神经毒性（如化疗诱导的周围神经病变（CIPN））中的作用的证据有限。我们在这里表明，顺铂治疗两个周期（累积剂量为 23mg/kg）会引起 Sprague-Dawley 大鼠的机械性痛觉过敏和热痛觉过敏。从顺铂处理的大鼠分离背根神经节（DRG）显示出在第 8 天（第一周期后）和第 18 天（第二周期后）SA-β-gal 的强烈上调，lmnb1 表达减少，cdkn1a 和 cdkn2a 的表达增加，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，与载体处理的大鼠相比，顺铂处理的大鼠的 KCl 诱发钙反应的幅度显著增加。与载体处理的大鼠相比，顺铂处理的大鼠的辣椒素诱发钙反应的幅度没有显著变化，但顺铂处理的大鼠的反应曲线下面积减小。需要更多支持 TIS 对治疗不良反应的贡献的证据，但应该鼓励使用衰老调节剂（衰老治疗剂）作为减轻化疗诱导的神经毒性的新型姑息治疗方法。
