Abstract
The present study was undertaken to investigate the anticancer activity of flexirubin produced by Chryseobacterium artocarpi CECT8497 and to explore its mechanism of action. The effect of flexirubin on cell proliferation of MCF-7 cells were evaluated by 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyl-tetrazolium bromide (MTT), sulforhodamine B (SRB) and lactate dehydrogenase (LDH) assays. Cell apoptosis was detected by DNA fragmentation and expression of apoptosis-related genes were assessed by RT-PCR. The study was further designed to appraise the anticancer activity of flexirubin against 7,12-di methylbenz( a) anthracene (DMBA) induced breast cancer in Sprague Dawley rats for 120 days. Treatment of cells at various concentrations (25 to 400 μg/ml) inhibited cell viability in a dose dependent manner. IC 50 values of flexirubin on human breast cancer MCF-7 cells obtained by MTT, SRB and LDH were 62, 71 and 48 μM respectively. DNA fragmentation was observed in MCF-7 cell line at 45 and 90 μg/ml concentration, while no DNA fragmentation was observed in untreated cells. Flexirubin treated cells exhibited considerable decrease in the level of anti-apoptotic protein BCL-2, a strong indication that the intrinsic apoptotic pathway may play a role in MCF-7 cells. The expression of p53, caspase 3 and BCL-2 was induced by flexirubin in a dose and time dependent manner. The compound flexirubin showed good affinity to the receptor due to more lipophilic character and hydrogen bonding. The results obtained in the molecular docking studies showed good correlation with in vitro and in vivo activity. Molecular docking showed that flexirubin was effective to control the over expression of anti-apoptotic protein MCL-1, suggesting its possible applications in cancer treatment. Our findings implement that flexirubin is a potential chemo-preventive agent against human breast cancer.
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