Antitumor Activity of K6, an Allylthiopyridazine Derivative, in Hep-G2 Cells-transplanted Nude Mice

In vitro cytotoxicity and in vivo growth-inhibitory effect of 3-methoxy-6-allylthiopyridazine (K6), an allylthiopyridazine derivative, were evaluated in human hepatocellular carcinoma Hep-G2 cell line and in nude mouse xenograft model, respectively, in comparison with doxorubicin. In vitro cytotoxicity, K6 (5-2,000 μM) and doxorubicin (0.05-10 μM) decreased tetrazolium conversion by viable cells to formazan in a dose-dependent manner. From a mechanistic study, the Hep-G2 cells exposed to K6 or doxorubicin underwent morphological changes, displaying elongation with filamentous protrusions. In addition, the cells showed chromatin condensation and fragmentation, producing apoptotic bodies. In vivo solid tumor xenograft model, the growth rate of tumor mass was significantly suppressed to the half level by daily oral administration of K6 (20-100 ㎎/㎏), which is comparable to the effect of intravenous treatment with doxorubicin (2 ㎎/㎏), resulting in the decrease in final tumor weights to 0.78 and 0.50 g by K6 (100 ㎎/㎏) and doxorubicin, respectively, compared with 1.32 g of control. Also, mean survival time of mice of control group (14.4 days) was doubled by treatment with K6 (27.2-29.4 days) or doxorubicin (28.8 days), leading to 100% increase in life span. Interestingly, daily oral treatment with a high dose (100 ㎎/㎏) of K6 did not induce testicular toxicity, in contrast to full degenerations of germ cells in atrophic testes intravenously exposed to doxorubicin at 4-6-day intervals, in addition to the emaciation and decrease in body weights of the animals. Taken together, K6, an allylthiopyridazine derivative originated from dially sulfide in garlic oil, could be a promising candidate for chemotherapy of hepatocellular carcinomas as an oral regimen. 키워드