School of Pharmaceutical Sciences, Universiti Sains Malaysia (USM), Minden 11800, Pulau Pinang, Malaysia.
Molecules. 2012 Mar 8;17(3):2939-54. doi: 10.3390/molecules17032939.
Despite the progress in colon cancer treatment, relapse is still a major obstacle. Hence, new drugs or drug combinations are required in the battle against colon cancer. α-Mangostin and betulinic acid (BA) are cytotoxic compounds that work by inducing the mitochondrial apoptosis pathway, and cisplatin is one of the most potent broad spectrum anti-tumor agents. This study aims to investigate the enhancement of BA cytotoxicity by α-mangostin, and the cytoprotection effect of α-mangostin and BA on cisplatin-induced cytotoxicity on HCT 116 human colorectal carcinoma cells. Cytotoxicity was investigated by the XTT cell proliferation test, and the apoptotic effects were investigated on early and late markers including caspases-3/7, mitochondrial membrane potential, cytoplasmic shrinkage, and chromatin condensation. The effect of α-mangostin on four signalling pathways was also investigated by the luciferase assay. α-Mangostin and BA were more cytotoxic to the colon cancer cells than to the normal colonic cells, and both compounds showed a cytoprotective effect against cisplatin-induced cytotoxicity. On the other hand, α-mangostin enhanced the cytotoxic and apoptotic effects of BA. Combination therapy hits multiple targets, which may improve the overall response to the treatment, and may reduce the likelihood of developing drug resistance by the tumor cells. Therefore, α-mangostin and BA may provide a novel combination for the treatment of colorectal carcinoma. The cytoprotective effect of the compounds against cisplatin-induced cytotoxicity may find applications as chemopreventive agents against carcinogens, irradiation and oxidative stress, or to neutralize cisplatin side effects.
尽管结肠癌的治疗取得了进展，但复发仍然是一个主要障碍。因此，需要新的药物或药物组合来对抗结肠癌。α-倒捻子素和白桦脂酸（BA）是细胞毒性化合物，通过诱导线粒体凋亡途径发挥作用，顺铂是最有效的广谱抗肿瘤药物之一。本研究旨在探讨 α-倒捻子素对 BA 细胞毒性的增强作用，以及 α-倒捻子素和 BA 对 HCT 116 人结直肠癌细胞中顺铂诱导的细胞毒性的细胞保护作用。通过 XTT 细胞增殖试验研究细胞毒性，通过 caspase-3/7、线粒体膜电位、细胞质收缩和染色质浓缩等早期和晚期标志物研究凋亡效应。还通过荧光素酶测定法研究了 α-倒捻子素对四种信号通路的影响。α-倒捻子素和 BA 对结肠癌细胞的细胞毒性比对正常结肠细胞更强，这两种化合物都显示出对顺铂诱导的细胞毒性的细胞保护作用。另一方面，α-倒捻子素增强了 BA 的细胞毒性和凋亡作用。联合治疗针对多个靶点，这可能提高对治疗的总体反应，并降低肿瘤细胞产生耐药性的可能性。因此，α-倒捻子素和 BA 可能为结直肠癌的治疗提供一种新的联合用药方案。化合物对顺铂诱导的细胞毒性的细胞保护作用可能作为化学预防剂应用于致癌物质、辐射和氧化应激的预防，或中和顺铂的副作用。
