Caffeine overcomes genistein-induced G2/M cell cycle arrest in breast cancer cells.

Although inhibition of tumor cell growth by genistein is mediated by different types of cell cycle arrest, its regulation of genes related to the cell cycle is not clear. In this study, genistein caused a concentration-dependent growth inhibition in the hormone-independent cell line MDA-MB-435S. Flow cytometric analysis showed that genistein induced a concentration-dependent accumulation of cells in the G2/M phase of the cell cycle. Caffeine enhanced the inhibition of cell proliferation induced by genistein. Caffeine alone did not have an appreciable effect on the phases of the cell cycle, but caffeine at 3 mM completely eliminated genistein-induced G2/M cell cycle arrest. cDNA microarrays were used to investigate the mechanism of genistein-induced, caffeine-negated G2/M arrest. We identified 12 genes, which had opposite responses to genistein and caffeine treatments. Among these, 5 genes were upregulated by genistein and downregulated by caffeine; 7 genes were downregulated by genistein and upregulated by caffeine. Reversal by caffeine of genistein-induced G2/M phase arrest in breast cancer cell lines could increase their sensitivity to genistein and enhance genistein-induced inhibition of cell growth. Genes that have opposite responses to genistein and caffeine may be involved in regulation of the G2/M phase of the cell cycle.