Studies On The Antitumor Activity And Preliminary Mechanism Of Anthracene Nucleus Rhamnoside Derivatives

Natural products, many of which are glycosylated, have promoted the development of a large number of effective drugs and promising leading compound with appreciating activities against cancerous diseases. Anthracene nucleus rhamnoside derivatives are a kind of compounds with good potent activities against cancerous diseases. Firstly, we. screened these compounds for their antitumor activities using sulfurhodamine B and MTT assays, the biological activity of these compounds was evaluated for their cytostatic effects against three tumor cell lines (HL-60, KB and MDA-MB-231). Some of the derivatives exhibited potent cytotoxicity and compound 326A showed the highest cytotoxicity. Further study with sulfurhodamine B and MTT assays showed that 326A elicited wide-spectrum in vitro antitumor activities against a panel of 18 human tumor cell lines and one normal cell lines with an average IC50 value of 1.5μM. Furthermore, it showed multi-drug resistant(MDR) activity against a MDR cell line(MCF-7/ADM), which was much lower than ADR. Compound 326 A was found to induce the apoptosis of the HL-60 cell line through flow cytometry. Besides, western blot detection on HL-60 and KB cells shows that caspase-8, caspase-9 and caspase-3 were all activated, indicating that both death receptor pathway and mitochondria pathway may be activated by 326A. The inhibitory activity of 326A toward TopoⅡwas demenstrated by topoisomeraseⅡ(TopoⅡ)-induced kDNA decatenation assay, which suggesting TopoⅡmay be the target of 326A. Further analyses byγ-H2AX assays showed that 326A induced DNA double strand breaks and may served as a TopoⅡpoison.In summary, the present study indicated that compound 326A exhibits strong antitumor activity in vitro, may induced apoptosis in HL-60 and KB cells by activating both death receptor pathway and mitochondria pathway.326A inhibited topoisomeraseⅡα(TopoⅡα)-mediated kDNA decatenation and induced DNA double strand breaks. The results above collectively suggest that 326A may exert antitumor effects by targets to topoisomeraseⅡin cells acting as a topoisomeraseⅡpoison. It is really a perspective compound with antitumor activity.