Curcumin, a natural polyphenol of turmeric, continues to receive considerable attention as potent antioxidant and anti-cancer agent. Numerous analogues of curcumin have been synthesized and screened for their improved biological activities. An assessment of anticancer activities of curcumin and its novel 15 analogues was conducted in vitro. Various biochemical and toxicological techniques were employed to assess the therapeutic action of the synthetic novel curcumin analogs in comparison to curcumin and Sorafenib� (a clinically approved drug). Inhibition of the cancer cell (HepG2) proliferation assessed by MTS assay showed that compound 2-[(E)-3-(4-hydroxyphenyl)acryloyl]-6-[1-(4-hydroxyphenyl)meth-(E)-ylidene]-cyclohexanone exhibits the trongest anticancer activity compared to curcumin and Sorafenib� (p<0.05). 2-[(E)-3-(3,4-Dimethoxyphenyl)acryloyl]-6-[1-(3,4-dimethoxyphenyl)meth-(E)-ylidene]cyclohexanone and curcumin showed the highest cytotoxic effects (p<0.05) in HepG2 cell line, analyzed by LDH release assay. All the curcumin analogues induced apoptosis in tumor cells by caspase-3 activation and DNA fragmentation. It was found that Sorafenib�, compounds 2-[(E)-(3-phenylacryloyl)]-5-[1-phenylmeth-(E)-ylidene]cyclopentanone and 2-((E)-3-p-tolylacryloyl)-6-[1-p-tolylmeth-(E)-ylidene]cyclohexanone induced the highest amount of apoptotic caspase-3 enzyme in cancer cells(p<0.05). Apoptosis in all drug candidates was further confirmed by florescence microscopy using annexin V and 7-ADD dyes. Flow cytometry was employed to analyze cell cycle and it was found that curcumin and its derivatives induced cell arrest at G0/G1 phase in cancer cells. Compounds 2-[(E)-3-(4-Chlorophenyl)acryloyl]-5-[1-(4-chlorophenyl)-meth-(E)-ylidene]-cyclopenta-none and 2-[(E)-(3-Phenylacryloyl)]-6-[1-phenylmeth-(E)-ylidene]cyclohexanone  were found to have the highest proportion of cells in apoptotic G0/G1 phase. These effects were also accompanied by catalytic inhibition of human topoisomerase II by all analyzed curcumin analogues. In addition, toxicology study was conducted to investigate toxicity of curcumin derivatives using normal human and rat hepatocytes. It was found that all compounds except 2-((E)-3-p-tolylacryloyl)-6-[1-p-tolylmeth-(E)-ylidene]cyclohexanonewere less cytotoxic than Sorafenib�. The compound 2-[(E)-3-(4-Hydroxyphenyl)acryloyl]-6-[1-(4-hydroxyphenyl)meth-(E)-ylidene]-cyclohexanone with enhanced biological activity and non-toxic manifestations emerged as the strongest drug candidate. The novel curcumin analogue 2-[(E)-3-(4-hydroxyphenyl)acryloyl]-6-[1-(4-hydroxyphenyl)meth-(E)-ylidene]-cyclohexanone was further assessed for its molecular pathway involved in antitumor activity using RT-PCR technique.

Antitumor activity of novel curcumin analogs in hepatocarcinoma (HepG2) cells

246th National Meeting (2013)

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