In vitro and in vivo anti-leukemic effects of cladoloside C2 are mediated by activation of Fas/ceramide synthase 6/p38 kinase/ c-Jun NH2-terminal kinase/caspase-8
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Seong-Hoon Yun1, Eun-Hye Sim1, Sang-Heum Han1, Tae-Rang Kim1, Mi-Ha Ju2, Jin-Yeong Han3, Jin-Sook Jeong2, Sung-Hyun Kim4, Alexandra S. Silchenko5, Valentin A. Stonik5 and Joo-In Park1
1Department of Biochemistry, Dong-A University College of Medicine, Busan, South Korea
2Department of Pathology, Dong-A University College of Medicine, Busan, South Korea
3Department of Laboratory Medicine, Dong-A University College of Medicine, Busan, South Korea
4Department of Internal Medicine, Dong-A University College of Medicine, Busan, South Korea
5G.B. Elyakov Pacific Institute of Bio-organic Chemistry, Far-Eastern Branch of the Russian Academy of Sciences, Vladivostok, Russia
Joo-In Park, email: [email protected]
Keywords: marine triterpene glycoside; ceramide synthase 6; JNK; caspase-8; anti-leukemic activity
Received: August 03, 2017 Accepted: November 14, 2017 Published: December 08, 2017
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.
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