Di Cesare Mannelli L, Zanardelli M, Failli P, Ghelardini C
Department of Preclinical and Clinical Pharmacology, University of Florence, 50139 Florence, Italy.
Department of Preclinical and Clinical Pharmacology, University of Florence, 50139 Florence, Italy.
Free Radic Biol Med. 2013 Aug;61:143-50. doi: 10.1016/j.freeradbiomed.2013.03.019. Epub 2013 Mar 31.
Oxaliplatin is a platinum-organic drug with antineoplastic properties used for colorectal cancer. With respect to the other platinum derivates oxaliplatin induces only a mild hematological and gastrointestinal toxicity. Its limiting side effect is its neurotoxicity, which results in a sensory neuropathy. Repeated oxaliplatin treatment in the rat led to a neuropathic pain characterized by a significant oxidative damage throughout the nervous system. The natural antioxidants silibinin and α-tocopherol reduce redox alteration and prevent pain. Starting from the "oxidative hypothesis" as a molecular basis of chemotherapy-induced neurotoxicity, we decided to explore deep inside the mechanisms of oxaliplatin neurotoxicity and search for a cellular system useful for screening antioxidant compounds that can reduce oxaliplatin neurotoxicity. Focusing on various constituents of the central nervous system, we used the neuronal-derived cell line SH-SY5Y and primary cultures of rat cortical astrocytes. Oxaliplatin significantly increased superoxide anion production and induced lipid peroxidation (malonyldialdehyde levels) and protein (carbonylated proteins) and DNA oxidation (8-OH-dG levels). Silibinin and α-tocopherol (10µM) were able to reduce the oxidative damage in both cell types. These antioxidants fully protected astrocytes from the caspase 3 apoptotic signaling activation induced by oxaliplatin. The damage prevention effects of silibinin and α-tocopherol on nervous system-derived cells did not interfere with the oxaliplatin antineoplastic in vitro mechanism as evaluated on a human colon adenocarcinoma cell line (HT29). Moreover, neither silibinin nor α-tocopherol modified the oxaliplatin-induced apoptosis in HT29 cells, suggesting a different antiapoptotic profile in normal vs tumoral cells for these antioxidant compounds. In conclusion, because data obtained in in vitro cellular models parallel the in vivo study we propose cell models to investigate oxaliplatin neurotoxicity and to screen possible therapeutic adjuvant agents.
奥沙利铂是一种具有抗肿瘤特性的铂类有机药物，用于治疗结直肠癌。与其他铂衍生物相比，奥沙利铂仅引起轻度的血液学和胃肠道毒性。其限制副作用是神经毒性，会导致感觉神经病变。在大鼠中重复给予奥沙利铂会导致神经性疼痛，其特征是整个神经系统出现明显的氧化损伤。天然抗氧化剂水飞蓟宾和α-生育酚可减少氧化还原改变并预防疼痛。基于“氧化假说”作为化疗诱导神经毒性的分子基础，我们决定深入探究奥沙利铂神经毒性的机制，并寻找一种可用于筛选能降低奥沙利铂神经毒性的抗氧化化合物的细胞系统。针对中枢神经系统的各种成分，我们使用了神经元衍生的细胞系SH-SY5Y和大鼠皮质星形胶质细胞的原代培养物。奥沙利铂显著增加了超氧阴离子的产生，并诱导了脂质过氧化（丙二醛水平）、蛋白质（羰基化蛋白质）和DNA氧化（8-羟基脱氧鸟苷水平）。水飞蓟宾和α-生育酚（10μM）能够降低两种细胞类型中的氧化损伤。这些抗氧化剂完全保护星形胶质细胞免受奥沙利铂诱导的半胱天冬酶3凋亡信号激活。水飞蓟宾和α-生育酚对神经源性细胞的损伤预防作用并未干扰在人结肠腺癌细胞系（HT29）上评估的奥沙利铂体外抗肿瘤机制。此外，水飞蓟宾和α-生育酚均未改变奥沙利铂诱导的HT29细胞凋亡，这表明这些抗氧化化合物在正常细胞与肿瘤细胞中的抗凋亡谱不同。总之，由于在体外细胞模型中获得的数据与体内研究结果相似，我们建议使用细胞模型来研究奥沙利铂神经毒性并筛选可能的治疗辅助剂。
