Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait.
Biomed Pharmacother. 2020 Jul;127:110210. doi: 10.1016/j.biopha.2020.110210. Epub 2020 May 11.
Paclitaxel-induced neuropathic pain (PINP) is a dose-limiting side effect that largely affects the patient's quality of life and may limit the use of the drug as a chemotherapeutic agent for treating metastatic breast cancer and other solid tumors. Recently, a putative role for the gaseous mediator hydrogen sulfide (HS) in nociception modulation has been suggested. The aim of the present study was to investigate the potential efficacy of the slow release HS donor GYY4137 to alleviate and prevent PINP. Female BALB/c mice that were intraperitoneally (i.p.) injected with paclitaxel (2 mg/kg) for 5 consecutive days developed thermal hyperalgesia, cold and mechanical allodynia and had reduced of HS, generation in the spinal cord and paw skin. Treatment of mice with established thermal hyperalgesia with GYY4137 or the analgesic positive control drug gabapentin produced antihyperalgesic activities. The antihyperalgesic activity of GYY4137 was antagonized by the ATP sensitive potassium channels (K channels) blocker glibenclamide. Co-treatment with GYY4137 and paclitaxel prevented the paclitaxel-induced decrease in HS, generation as well as the paclitaxel-induced thermal hyperalgesia, cold allodynia and mechanical allodynia. GYY4137 enhanced paclitaxel's anti-proliferative effects against the breast cancer cell line MCF-7. The present results suggest that GYY4137 alleviates paclitaxel-induced thermal hyperalgesia, via K channels. GYY4137 prevents PINP possibly by blocking the paclitaxel-induced reduction in the generation of HS, in the tissues, while enhancing the anti-cancer activity of paclitaxel, and therefore warrants further research as a candidate for prevention of PINP in clinical settings.
紫杉醇诱导的神经性疼痛（PINP）是一种剂量限制的副作用，它在很大程度上影响了患者的生活质量，并可能限制了该药作为治疗转移性乳腺癌和其他实体瘤的化疗药物的应用。最近，有研究提出气态递质硫化氢（HS）在痛觉调制中具有潜在作用。本研究旨在探讨缓激肽 HS 供体 GYY4137 缓解和预防 PINP 的潜在疗效。雌性 BALB/c 小鼠连续 5 天腹腔注射紫杉醇（2 mg/kg）后，出现热痛觉过敏、冷和机械性痛觉过敏，脊髓和爪皮 HS 生成减少。用 GYY4137 或镇痛阳性对照药物加巴喷丁治疗已建立热痛觉过敏的小鼠可产生抗痛觉过敏作用。GYY4137 的抗痛觉过敏作用被 ATP 敏感钾通道（K 通道）阻滞剂格列本脲拮抗。GYY4137 与紫杉醇联合治疗可预防紫杉醇引起的 HS 生成减少以及紫杉醇引起的热痛觉过敏、冷觉过敏和机械性痛觉过敏。GYY4137 增强了紫杉醇对乳腺癌细胞系 MCF-7 的抗增殖作用。本研究结果表明，GYY4137 通过 K 通道缓解紫杉醇诱导的热痛觉过敏。GYY4137 可能通过阻断紫杉醇引起的组织中 HS 生成减少，同时增强紫杉醇的抗癌活性，从而预防 PINP，因此值得进一步研究，作为临床预防 PINP 的候选药物。
