Acklin Scarlett, Sadhukhan Ratan, Du Wuying, Patra Mousumi, Cholia Ravi, Xia Fen
Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Neurooncol Adv. 2022 Jun 27;4(1):vdac101. doi: 10.1093/noajnl/vdac101. eCollection 2022 Jan-Dec.
Chemotherapy-induced peripheral neuropathy represents a major impairment to the quality of life of cancer patients and is one of the most common dose-limiting adverse effects of cancer treatment. Despite its prevalence, no effective treatment or prevention strategy exists. We have previously provided genetic evidence that the NAD-dependent deacetylase, SIRT2, protects against cisplatin-induced peripheral neuronal cell death and neuropathy by enhancing nucleotide excision repair. In this study, we aimed to examine whether pharmacologic activation of SIRT2 would provide effective prevention and treatment of cisplatin-induced peripheral neuropathy (CIPN) without compromising tumor cell cytotoxic response to cisplatin.
Using von Frey and dynamic hot plate tests, we studied the use of nicotinamide riboside (NR) to prevent and treat CIPN in a mouse model. We also performed cell survival assays to investigate the effect of NAD supplementation on cisplatin toxicity in neuronal and cancer cells. Lewis lung carcinoma model was utilized to examine the effect of NR treatment on in vivo cisplatin tumor control.
We show that NR, an NAD precursor and pharmacologic activator of SIRT2, effectively prevents and alleviates CIPN in mice. We present in vitro and in vivo genetic evidence to illustrate the specific dependence on SIRT2 of NR-mediated CIPN mitigation. Importantly, we demonstrate that NAD mediates SIRT2-dependent neuroprotection without inhibiting cisplatin cytotoxic activity against cancer cells. NAD may, in fact, further sensitize certain cancer cell types to cisplatin.
Together, our results identify SIRT2-targeted activity of NR as a potential therapy to alleviate CIPN, the debilitating and potentially permanent toxicity.
化疗引起的周围神经病变是癌症患者生活质量的主要损害因素，也是癌症治疗中最常见的剂量限制性不良反应之一。尽管其普遍存在，但尚无有效的治疗或预防策略。我们之前已提供遗传学证据表明，烟酰胺腺嘌呤二核苷酸（NAD）依赖性脱乙酰酶SIRT2通过增强核苷酸切除修复来保护细胞免受顺铂诱导的周围神经元细胞死亡和神经病变。在本研究中，我们旨在探讨SIRT2的药物激活是否能有效预防和治疗顺铂诱导的周围神经病变（CIPN），同时又不损害肿瘤细胞对顺铂的细胞毒性反应。
我们使用von Frey和动态热板试验，研究了烟酰胺核糖（NR）在小鼠模型中预防和治疗CIPN的作用。我们还进行了细胞存活试验，以研究补充NAD对神经元和癌细胞中顺铂毒性的影响。利用Lewis肺癌模型来研究NR治疗对体内顺铂肿瘤控制的影响。
我们发现，NR作为SIRT2的NAD前体和药物激活剂，能有效预防和减轻小鼠的CIPN。我们提供了体外和体内遗传学证据，以说明NR介导的CIPN减轻对SIRT2的特异性依赖性。重要的是，我们证明NAD介导SIRT2依赖性神经保护作用，而不抑制顺铂对癌细胞的细胞毒性活性。事实上，NAD可能会使某些癌细胞类型对顺铂更敏感。
总之，我们的研究结果表明，NR靶向SIRT2的活性是缓解CIPN这种使人衰弱且可能永久性毒性的潜在疗法。
