Cheng Xiaolan, Huo Jiege, Wang Dawei, Cai Xueting, Sun Xiaoyan, Lu Wuguang, Yang Yang, Hu Chunping, Wang Xiaoning, Cao Peng
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese MedicineNanjing, China.
Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese MedicineNanjing, China.
Front Pharmacol. 2017 Jun 7;8:344. doi: 10.3389/fphar.2017.00344. eCollection 2017.
Oxaliplatin is clinically compelling because of severe peripheral neuropathy. The side effect can result in dosage reductions or even cessation of chemotherapy, and no effective treatments are available. AC591 is a standardized extract of Huangqi Guizhi Wuwu decoction, an herbal formula recorded in "Synopsis of the Golden Chamber" for improving limb numbness and pain. In this study, we investigated whether AC591 could protect against oxaliplatin-induced peripheral neuropathy. To clarify it, a rat model of oxaliplatin-induced peripheral neuropathy was established, and neuroprotective effect of AC591 was studied. Our results showed that pretreatment with AC591 reduced oxaliplatin-induced cold hyperalgesia, mechanical allodynia as well as morphological damage of dorsal root ganglion. Microarray analysis indicated the neuroprotective action of AC591 depended on the modulation of multiple molecular targets and pathways involved in the downregulation of inflammation and immune response. Moreover, AC591 enhanced the antitumor activity of oxaliplatin to some extent in Balb/c mice bearing CT-26 carcinoma cells. The efficacy of AC591 is also investigated in 72 colorectal cancer patients. After four cycles of treatment, the percentage of grades 1-2 neurotoxicity in AC591-treated group ( = 36) was 25%, whereas in the control group the incidence was 55.55% ( < 0.01) ( = 36). No significant differences in the tumor response rate between the two groups were found. These evidences suggested that AC591 can prevent oxaliplatin-induced neuropathy without reducing its antitumor activity, and may be a promising adjuvant to alleviate sensory symptoms in clinical practice.
由于严重的周围神经病变，奥沙利铂在临床上存在局限性。这种副作用可能导致化疗剂量减少甚至化疗中断，且目前尚无有效的治疗方法。AC591是黄芪桂枝五物汤的标准化提取物，黄芪桂枝五物汤是《金匮要略》中记载的用于改善肢体麻木和疼痛的中药方剂。在本研究中，我们调查了AC591是否可以预防奥沙利铂诱导的周围神经病变。为了阐明这一点，我们建立了奥沙利铂诱导的周围神经病变大鼠模型，并研究了AC591的神经保护作用。我们的结果表明，AC591预处理可减轻奥沙利铂诱导的冷痛觉过敏、机械性异常性疼痛以及背根神经节的形态学损伤。基因芯片分析表明，AC591的神经保护作用取决于对多个分子靶点和参与下调炎症和免疫反应的信号通路的调节。此外，AC591在携带CT-26癌细胞的Balb/c小鼠中在一定程度上增强了奥沙利铂的抗肿瘤活性。我们还在72例结直肠癌患者中研究了AC591的疗效。经过四个周期的治疗，AC591治疗组（n = 36）1-2级神经毒性的发生率为25%，而对照组的发生率为55.55%（P < 0.01）（n = 36）。两组之间的肿瘤反应率没有显著差异。这些证据表明，AC591可以预防奥沙利铂诱导的神经病变而不降低其抗肿瘤活性，并且可能是临床实践中缓解感觉症状的一种有前景的辅助药物。
