Abstract
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.
Highlights
Leukemia is a heterogeneous clonal disorder characterized by defects in cell differentiation and the death of hematopoietic progenitor cells
These data suggest that cladoloside C2-induced apoptosis in K562 and HL-60 cells is influenced by a caspase-dependent mechanism involving an extrinsic pathway
We further investigated how cladoloside C2 treatment affected the levels of the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1), B-cell lymphoma-2 (Bcl-2), and B-cell lymphoma extra large (Bcl-xL); and the proapoptotic protein Bcl2-associated X protein (Bax)
Summary
Leukemia is a heterogeneous clonal disorder characterized by defects in cell differentiation and the death of hematopoietic progenitor cells. There remains a need for new therapeutic agents and strategies to improving the leukemia cure rate. The tumor-suppressor lipid ceramide reportedly exhibits potent growth inhibition effects in a variety of cell types [3]. Ceramide can be generated by either ceramide synthases or sphingomyelinases [4, 5]. Sphingomyelinases (SMases) are categorized as acid, neutral, or alkaline [6, 7], according to the pH at which they show maximum activity [8]. Many anticancer agents increase ceramide levels to varying extents in different types of cancer cells [9]. The pharmacological modulation of sphingolipid metabolism to enhance ceramide in tumor cells represents a novel therapeutic approach
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