Evaluation of novel isoquinolones as cytotoxic agents in hepatocellular carcinoma


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Mai Ali1,Asma Belgath1,Sally Freeman1,Katherine Finegan1,Ian Stratford1
1University of Manchester

Abstract

Background

Hepatocellular carcinoma accounts for 90% of primary liver cancers, being the fifth most common cancer in the world and the second cause of cancer-related mortality. NRH: quinone oxidoreductase 2 (NQO2) is a detoxifying enzyme ubiquitously produced in human tumours, and has been found to be inhibited by resveratrol. A set of 3-arylisoquinolones with methoxy- and/or fluoro substituents was designed and synthesised as resveratrol analogues to assess their ability to inhibit NQO2 as a way to trigger cancer kill.

Method

Dichlorophenolindophenol (DCPIP) spectrophotometric assay was used to evaluate the inhibitory potency of the 3-arylisoquinolines against NQO2 in a cell free system. The anticancer activity towards human liver cancer cell lines, namely Hep G2, Hep 3B2 and SNU 423, was evaluated using SRB and colony formation assays. The effect of the compounds on DNA binding and cell cycle was also studied.

Results

The 3-arylisoquinolones were inactive as NQO2 inhibitors and they did not bind to DNA; however assays in liver cancer cell lines showed a substantial difference in cell toxicity, with the meta-substituted analogues being significantly more active than the equivalent para-analogues. The meta-methoxy compound induced a dose-dependent cell cycle arrest at G2/M phase, which was not seen at even higher concentrations for the corresponding para-methoxy compound.

Conclusion

These results confirm that subtle structural changes in the 3-arylisoquinolones can cause significant changes in cell cycle, and consequently cytotoxicity. Further experiments need to be done to elucidate deeper the mode of toxicity.