A study on botanical alkyl hydroquinones as anti-cancer drugs

• Main Authors: Cheng-Po Huang, 黃政博
• Other Authors: 林淑萍
• Format: Others
• Language: zh-TW
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/29448635183073757363

博士 === 臺灣大學 === 醫學檢驗暨生物技術學研究所 === 96 === Cytotoxic alkyl hydroquinone compounds have been isolated from many plants. We previously isolated 3 structurally similar cytotoxic alkyl hydroquinone compounds from the sap of the lacquer tree Rhus succedanea L. belonging to the sumac family. Each of them has an unsaturated alkyl chain attached to the 2-position of a hydroquinone ring. One of these isolates, 10′(Z),13′(E),15’(E)-heptadecatrienylhydroquinone [HQ17(3)], being the most cytotoxic, was chosen for studying the anticancer mechanism of these compounds. In this study, we have shown that HQ17(3) was a topoisomerase (Topo) II poison and the inhibition was irreversible through the accumulation of Topo II-DNA cleavable complexes. A cell-based assay showed that HQ17(3) inhibited the growth of leukemia HL-60 cells with an EC50 of 0.9 μM, inhibited theTopo-II deficient cells HL-60/MX2 with an EC50 of 9.6 μM, and exerted no effect on peripheral blood mononuclear cells at concentrations up to 50 μM. Therefore, the inhibition of Topo II plays an important role in HQ17(3) induced cell death. Since HQ17(3) was structurally similar to HQ, the comparison of the effects induced by HQ and HQ17(3) was demonstrated.HQ17(3) presents the same ability to trigger oxidative damage as HQ. However, when given an anti-oxidant agent, N-acetylcysteine, the cytotoxic effect of HQ can be significantly diminished but not HQ17(3). Therefore, HQ17(3) exhibit an ability to induce cell death in cancer cell through different pathway from HQ. In another part of this study, HQ17(3) was found to induce apoptosis in hepatoma cell line, Huh7. After HQ17(3) treatment, over expression of several DNA damage-related and apoptosis-related genes can be detected by cDNA microarray. Besides, the activation of caspase pathway was also detected. In animal experiments, HQ17(3) can inhibit the growth and metastasis of Lewis lung carcinoma cells induced tumor. In F344 rats, intraperitoneal injection of HQ17(3) for 28 days induced no clinical signs of toxicity. These results indicated that HQ17(3) is a potential anticancer agent, and its structural features could be a model for anticancer drug design.