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 g arlic oil, were shown to inhibit the proliferation of tumour cells. Since h epatocellular carcinoma is one of the most lethal malignancies and there is no effective preventive measure to date. we wished to pursue the chemoprev entive potential of the synthetic allylthiopyridazine derivatives (K compou nds) on hepatocarcinoma cells. Here. we report that the K compounds efficie ntly inhibited SK-Hep-1 cell proliferation through induction of apoptosis. Increased chain length at the 3-position of allylthiopyridazine ring improv ed the potency of growth inhibition. K compounds downregulated Bcl-2. while Bax remained unchanged, reducing the ratio of Bcl-2 to Bax. We also provid e evidence that the K compound-induced apoptosis involves cytochrome c rele ase and caspase-3 activation. These results suggest that the allythiopyrida zine derivatives, especially 3-propoxy-6-allylthiopyridazine, induce apopto sis in SK-Hep-1 cells through a caspase-3-dependent mechanism, which may co ntribute to the chemopreventive function for hepatocellular carcinoma. (C) 2001 Elsevier Science Ltd. All rights reserved.