Li Lin-Na, Zhang Hua-Dong, Yuan Shou-Jun, Tian Zeng-Yue, Wang Lin, Sun Zhi-Xian
Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing, China.
Int J Cancer. 2007 Sep 15;121(6):1360-5. doi: 10.1002/ijc.22804.
Artesunate (ART), a remarkable antimalarial agent, also inhibited the growth of human colorectal carcinoma. As determined by MTT assay, flow cytometry analysis on apoptosis and indirect immunofluorescence analysis on the proliferation-associated marker Ki67, ART suppressed the proliferation and promoted the apoptosis of colorectal cancer cells in a dose-dependent manner. Furthermore, immunofluorescence analysis on beta-catenin and RT-PCR analysis on Wnt/beta-catenin target genes demonstrated ART translocated beta-catenin from nucleus to adherent junctions of membrane and reduced transcription mediated by beta-catenin. These results suggested the anticancer activity of ART correlated with the inhibition of hyperactive Wnt/beta-catenin signaling pathway. In vivo, ART significantly slowed the growth of colorectal tumor xenografts. Bioluminescent imaging also revealed that ART decreased the physiological activity of tumor xenografts and delayed spontaneous liver metastasis. These antitumor effects were related to the membranous translocation of beta-catenin and the inhibition of the unrestricted activation of Wnt/beta-catenin pathway, which was confirmed by the immunohistochemical staining of tumor tissues. These results and the known low toxicity are clues that ART might be a promising candidate drug for the treatment of colorectal carcinoma.
青蒿琥酯（ART）是一种显著的抗疟药，它也能抑制人结肠直肠癌的生长。通过MTT法、凋亡的流式细胞术分析以及增殖相关标志物Ki67的间接免疫荧光分析确定，ART以剂量依赖的方式抑制结肠癌细胞的增殖并促进其凋亡。此外，β-连环蛋白的免疫荧光分析以及Wnt/β-连环蛋白靶基因的RT-PCR分析表明，ART使β-连环蛋白从细胞核转移至细胞膜的黏附连接部位，并减少由β-连环蛋白介导的转录。这些结果表明，ART的抗癌活性与抑制过度活跃的Wnt/β-连环蛋白信号通路相关。在体内，ART显著减缓了结肠肿瘤异种移植瘤的生长。生物发光成像还显示，ART降低了肿瘤异种移植瘤的生理活性并延迟了自发肝转移。这些抗肿瘤作用与β-连环蛋白的膜转位以及Wnt/β-连环蛋白通路不受限制的激活受到抑制有关，这一点通过肿瘤组织的免疫组化染色得到证实。这些结果以及已知的低毒性表明，ART可能是一种有前景的治疗结肠直肠癌的候选药物。
