Chemopreventive allylthiopyridazine derivatives induce apoptosis in SK-Hep-1 hepatocarcinoma cells through a caspase-3-dependent mechanism

Dietary organosulphur compounds including diallylsulphide. a component of garlic oil, were shown to inhibit the proliferation of tumour cells. Since hepatocellular carcinoma is one of the most lethal malignancies and there is no effective preventive measure to date. we wished to pursue the chemopreventive potential of the synthetic allylthiopyridazine derivatives (K compounds) on hepatocarcinoma cells. Here. we report that the K compounds efficiently inhibited SK-Hep-1 cell proliferation through induction of apoptosis. Increased chain length at the 3-position of allylthiopyridazine ring improved the potency of growth inhibition. K compounds downregulated Bcl-2. while Bax remained unchanged, reducing the ratio of Bcl-2 to Bax. We also provide evidence that the K compound-induced apoptosis involves cytochrome c release and caspase-3 activation. These results suggest that the allythiopyridazine derivatives, especially 3-propoxy-6-allylthiopyridazine, induce apoptosis in SK-Hep-1 cells through a caspase-3-dependent mechanism, which may contribute to the chemopreventive function for hepatocellular carcinoma. (C) 2001 Elsevier Science Ltd. All rights reserved.