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Mar. Drugs 2018, 16(4), 123; https://doi.org/10.3390/md16040123

Holotoxin A1 Induces Apoptosis by Activating Acid Sphingomyelinase and Neutral Sphingomyelinase in K562 and Human Primary Leukemia Cells

1
Department of Biochemistry, Dong-A University College of Medicine, Busan 49201, Korea
2
Department of Laboratory Medicine, Dong-A University College of Medicine, Busan 49201, Korea
3
Department of Internal Medicine, Dong-A University College of Medicine, Busan 49201, Korea
4
G.B. Elyakov Pacific Institute of Bioorganic Chemistry, Far-Eastern Branch of the Russian Academy of Sciences, Vladivostok 690022, Russia
*
Author to whom correspondence should be addressed.
Received: 22 February 2018 / Revised: 29 March 2018 / Accepted: 4 April 2018 / Published: 10 April 2018
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Abstract

Marine triterpene glycosides are attractive candidates for the development of anticancer agents. Holotoxin A1 is a triterpene glycoside found in the edible sea cucumber, Apostichopus (Stichopus) japonicus. We previously showed that cladoloside C2, the 25(26)-dihydro derivative of holotoxin A1, induced apoptosis in human leukemia cells by activating ceramide synthase 6. Thus, we hypothesized that holotoxin A1, which is structurally similar to cladoloside C2, might induce apoptosis in human leukemia cells through the same molecular mechanism. In this paper, we compared holotoxin A1 and cladoloside C2 for killing potency and mechanism of action. We found that holotoxin A1 induced apoptosis more potently than cladoloside C2. Moreover, holotoxin A1 induced apoptosis in K562 cells by activating caspase-8 and caspase-3, but not by activating caspase-9. During holotoxin A1-induced apoptosis, acid sphingomyelinase (SMase) and neutral SMase were activated in both K562 cells and human primary leukemia cells. Specifically inhibiting acid SMase and neutral SMаse with chemical inhibitors or siRNAs significantly inhibited holotoxin A1–induced apoptosis. These results indicated that holotoxin A1 might induce apoptosis by activating acid SMase and neutral SMase. In conclusion, holotoxin A1 represents a potential anticancer agent for treating leukemia. Moreover, the aglycone structure of marine triterpene glycosides might affect the mechanism involved in inducing apoptosis. View Full-Text
Keywords: marine triterpene glycoside; acid sphingomyelinase; neutral sphingomyelinase; apoptosis; leukemia marine triterpene glycoside; acid sphingomyelinase; neutral sphingomyelinase; apoptosis; leukemia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Yun, S.-H.; Sim, E.-H.; Han, S.-H.; Han, J.-Y.; Kim, S.-H.; Silchenko, A.S.; Stonik, V.A.; Park, J.-I. Holotoxin A1 Induces Apoptosis by Activating Acid Sphingomyelinase and Neutral Sphingomyelinase in K562 and Human Primary Leukemia Cells. Mar. Drugs 2018, 16, 123.

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