Opposing Effects of ERK and p38 MAP Kinases on HeLa Cell Apoptosis Induced by Dipyrithione

Dipyrithione (2, 2'-dithiobispyridine-1, 1'-dioxide, PTS2), a pyrithione derivate, is highly bactericidal and fungicidal. In this study we examined its apoptotic effect on HeLa cells. PTS2 induced HeLa cell death in a dose and time dependent manner. ERK1/2 and p38 were markedly activated, but little JNK1/2 activation was detected. Suppression of p38 activation by SB203580 reduced the extent of apoptosis of the HeLa cells and also prevented induction of p21, release of cytochrome c, and cleavage of caspase-3 and PARP. Inhibition of ERK1/2 with PD98059 increased apoptosis, indicating that ERK1/2 activation has an anti-apoptotic effect on PTS2-induced HeLa cell apoptosis. PTS2 also inhibited murine sarcoma 180 and hepatoma 22 tumor growth in an animal tumor model. Our findings indicate that PTS2 possesses anti-tumor activity, that caspase-3 and poly (ADP-ribose) polymerase (PARP) are involved in PTS2-induced HeLa cell apoptosis and that ERK1/2 and p38 have opposing effects on this apoptosis.