Genistein Reinforces the Inhibitory Effect of Cisplatin on LiverCancer Recurrence and Metastasis after Curative Hepatectomy

Background: The high recurrence rate after hepatic resection in hepatocellular carcinoma (HCC) is a majorobstacle to improving prognosis. The objective of the present study was to explore the function of genistein, asoy-derived isoflavone, in enhancing the inhibitory effect of cisplatin on HCC cell proliferation and on tumorrecurrence and metastasis in nude mice after curative hepatectomy.
Methods: Proliferation of human HCCcells (HCCLM3) was detected by 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay.Synergistic effects of genistein and cisplatin were evaluated with the median-effect formula. Nude mice bearinghuman HCC xenografts underwent tumour resection (hepatectomy) 10 days post implantation, then receivedintraperitoneal administration of genistein or cisplatin alone or the combination of the two drugs. 33 days aftersurgery, recurrent tumours and pulmonary metastasis were evaluated individually. MMP-2 level in recurrenttumours was detected by immunohistochemistry and real-time PCR; MMP-2 expression in HCCLM3 was detectedby immunocytochemistry.
Results: Genistein and cisplatin both suppressed the growth and proliferation ofHCCLM3 cells. The two drugs exhibited synergistic effects even at relatively low concentrations. In vivo, mice inthe combined genistein and cisplatin group had a smaller volume of liver recurrent tumors and fewer pulmonarymetastatic foci compared with single drug treated groups. Cisplatin upregulated the expression of MMP-2 in bothrecurrent tumours and HCCLM3, while genistein abolished cisplatin-induced MMP-2 expression.
Conclusions:Genistein reinforced the inhibitory effect of cisplatin on HCC cell proliferation and tumour recurrence andmetastasis after curative hepatectomy in nude mice, possibly through mitigation of cisplatin-induced MMP-2upregulation.