Department of General Surgery, Shanxian Center Hospital, Heze, China.
Department of General surgery, Heze Second People's Hospital, Heze, China.
Biomed Pharmacother. 2018 Jul;103:67-74. doi: 10.1016/j.biopha.2018.03.110. Epub 2018 Apr 7.
5-Fluorouracil (5-Fu) and cisplatin (DDP) as important therapies in treatment of human gastric cancer have been widely determined. However, the therapeutic effects are usually hampered due to drug resistance or toxicity at high concentrations for application. Avicularin (AL, quercetin-3-α-l-arabinofuranoside), a bio-active flavonol isolated from a number of plants, has been reported to display diverse pharmacological properties. In this study, we explored the hypothesis by which AL reversed 5-Fu or DDP resistance in gastric cancer and the underlying molecular mechanism. Here, in vitro, the drug-resistant cancer cells were incubated to AL or DDP alone or the combination of AL and DDP. Then, MTT, colony formation, Hoechst 33258, flow cytometry and western blot analysis were used to investigate the effects of AL in the regulation of drug-resistance gastric cancer cells. The results indicated that AL treatment markedly re-sensitizes the drug resistant cells (SGC-7901/5-Fu and SGC-7901/DDP) to cytotoxicity of 5-Fu or DDP. Molecular mechanism analysis indicated that AL and DDP combination treatment enhanced apoptosis in SGC-7901/DDP cells, accompanied with the up-regulation of cleaved Caspase-3 and PARP, as well as the activation of pro-apoptotic signals, including Bax and BOK. Significantly, down regulation of Bax or BOK expressions using Bax siRNA or BOK siRNA decreased the inhibitory role of DDP in apoptosis of SGC-7901/DDP cells pretreated with AL, demonstrating that AL-reversed DDP resistance was associated with Bax and BOK expression. In vivo, AL and DDP combination significantly reduced gastric tumor growth. Immunohistochemical analysis indicated that co-treatment of AL and DDP significantly induced apoptosis, and reduced tumor cell proliferation in tumor tissue samples. Furthermore, we also found that the Bax, BOK, cleaved Caspase-3 and PARP expression in tumor tissues were highly induced by AL and DDP co-treatment. Together, our findings may provide a novel combination therapeutic strategy in treatment of human gastric cancer.
5-氟尿嘧啶（5-Fu）和顺铂（DDP）作为治疗人类胃癌的重要治疗方法已得到广泛确定。然而，由于耐药性或高浓度毒性，其治疗效果通常受到阻碍。鸡脚槲皮素（AL，槲皮素-3-α-L-阿拉伯呋喃糖苷）是一种从多种植物中分离得到的生物活性类黄酮，已被报道具有多种药理作用。在本研究中，我们通过假设 AL 逆转胃癌中 5-Fu 或 DDP 耐药性及其潜在的分子机制来探索这一假说。在体外，将耐药性癌细胞与 AL 或 DDP 单独或 AL 和 DDP 的组合孵育。然后，使用 MTT、集落形成、Hoechst 33258、流式细胞术和 Western blot 分析来研究 AL 在调节耐药性胃癌细胞中的作用。结果表明，AL 处理显著使耐药细胞（SGC-7901/5-Fu 和 SGC-7901/DDP）对 5-Fu 或 DDP 的细胞毒性重新敏感。分子机制分析表明，AL 和 DDP 联合治疗增强了 SGC-7901/DDP 细胞的凋亡，伴随着 cleaved Caspase-3 和 PARP 的上调，以及促凋亡信号的激活，包括 Bax 和 BOK。值得注意的是，使用 Bax siRNA 或 BOK siRNA 下调 Bax 或 BOK 的表达降低了 AL 预处理的 SGC-7901/DDP 细胞中 DDP 对凋亡的抑制作用，表明 AL 逆转 DDP 耐药性与 Bax 和 BOK 的表达有关。在体内，AL 和 DDP 联合显著减少胃肿瘤生长。免疫组织化学分析表明，AL 和 DDP 联合治疗显著诱导肿瘤组织样本中的细胞凋亡，并减少肿瘤细胞增殖。此外，我们还发现 AL 和 DDP 联合治疗可高度诱导肿瘤组织中 Bax、BOK、cleaved Caspase-3 和 PARP 的表达。总之，我们的研究结果为治疗人类胃癌提供了一种新的联合治疗策略。
