We previously demonstrated that the quinovose-containing hexaoside stichoposide C (STC) is a more potent anti-leukemic agent than the glucose-containing stichoposide D (STD), and that these substances have different molecular mechanisms of action. In the present study, we investigated the novel marine triterpene glycoside cladoloside C₂ from Cladolabes schmeltzii, which has the same carbohydrate moiety as STC. We assessed whether cladoloside C₂ could induce apoptosis in K562 and HL-60 cells. We also evaluated whether it showed antitumor action in mouse leukemia xenograft models, and its molecular mechanisms of action. We investigated the molecular mechanism behind cladoloside C₂-induced apoptosis of human leukemia cells, and examined the antitumor effect of cladoloside C₂ in a HL-60 and K562 leukemia xenograft model. Cladoloside C₂ dose- and time-dependently induced apoptosis in the analyzed cells, and led to the activation of Fas/ceramide synthase 6 (CerS6)/p38 kinase/JNK/caspase-8. This cladoloside C₂-induced apoptosis was partially blocked by specific inhibition by Fas, CerS6, and p38 siRNA transfection, and by specific inhibition of JNK by SP600125 or dominant negative-JNK transfection. Cladoloside C₂ exerted antitumor activity through the activation of Fas/CerS6/p38 kinase/JNK/caspase-8 without showing any toxicity in xenograft mouse models. The antitumor effect of cladoloside C₂ was reversed in CerS6 shRNA-silenced xenograft models. Our results suggest that cladoloside C2 has in vitro and in vivo anti-leukemic effects due to the activation of Fas/CerS6/p38 kinase/JNK/caspase-8 in lipid rafts. These findings support the therapeutic relevance of cladoloside C₂ in the treatment of human leukemia.

#	Concept	H-Index	Publications	Citations
1	Medicine	1	1	51
2	Cell Biology	1	1	51
3	Gastroenterology	1	1	51
4	Pathology	1	1	51
5	Epigenetic Regulation	1	1	51

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