P38 MAP kinase mediates apoptosis after genipin treatment in non-small-cell lung cancer H1299 cells via a mitochondrial apoptotic cascade

Genipin,an active constituent of gardenia fruit,has been reported to show an antitumor effect in several cancer cell systems. here,we demonstrate how genipin exhibits a strong apoptotic cell death effect in human non-small-cell lung cancer h1299 cells. genipin-mediated decrease in cell viability was observed through apoptosis as demonstrated by induction of a sub-g1 peak through flow cytometry,dna fragmentation measured by tunel assay,and cleavage of poly adp-ribose-polymerase. during genipin-induced apoptosis,the mitochondrial execution pathway was activated by caspase-9 and-3 activation as examined by a kinetic study,cytochrome c release,and a dose-dependent increase in bax/bcl-2 ratio. a search for the downstream pathway reveals that genipin-induced apoptosis was mediated by an increase in phosphorylated p38mapk expression,which further activated downstream signaling by phosphorylating atf-2. sb203580,a p38mapk inhibitor,markedly blocked the formation of tunel-positive apoptotic cells in genipin-treated cells. besides,the interference of p38mapk inhibited bax expression and cytochrome c release. altogether,our observations imply that genipin causes increased levels of bax in response to p38mapk signaling,which results in the initiation of mitochondrial death cascade,and therefore it holds promise as a potential chemotherapeutic agent for the treatment of h1299 cells. © the japanese pharmacological society.