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

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.

Distribution of Saponins in the Sea Cucumber Holothuria lessoni; the Body Wall Versus the Viscera, and Their Biological Activities

“…Triterpene glycosides of sea cucumber are known to possess a broad range of medicinal and physiological activities [ 10 , 11 ]. The medical potency of sea cucumber saponins exhibits plentiful health benefits due to their cardiovascular, ant-diabetic, hypoglycaemia, anti-oxidant, anti-asthma, anti-eczema, anti-inflammatory, anti-arthritic, anti-diabetics, cholesterol-lowering effect, immunomodulator, cytotoxic, anti-parasitic, anti-viral, antifungal [ 7 , 12 ], anticancer [ 13 , 14 ], anti-angiogenesis, anti-proliferative [ 15 ], and anti-dementia activities [ 2 ]. According to the literature, saponins also possess neuroprotective effects on the diminution of central nervous system disorders, namely Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and strokes [ 16 ].…”

The Anticancer Drug Discovery Potential of Marine Invertebrates from Russian Pacific

“…Another triterpene glycoside from the edible sea cucumber Apostichopus japonicus collected from Posiet Bay, Sea of Japan, holotoxin A1 induces apoptosis in human leukemic and colorectal cancer cells at sub-micromolar concentrations (IC 50 ranging from 20nM to 1 μM depending on the cell line) [50,51]. Holotoxin A1 was found to induce apoptosis through activation of acid sphingomyelinase and neutral sphingomyelinase.…”

“…Holotoxin A1 was found to induce apoptosis through activation of acid sphingomyelinase and neutral sphingomyelinase. The compound was also highly potent against a set of primary patient leukemic cells, but not normal hematopoietic progenitor cells, highlighting its potential for further drug development [51].…”

“…Some species of holothurians, for example, are subject to extensive cultivation due to the high gastronomic demand—in the Russian Far East this is the case for the sea cucumber Apostichopus japonicus [95,96]. As discussed above, this edible sea cucumber is the source of holotoxin A1 with interesting anticancer properties [50,51], which further adds to the label of A. japonicus and several other holothurians as functional foods [97,98,99]. The vast expertise accumulated in the cultivation of holothurians can be applied to new species of this class, which may emerge as the source of promising compounds.…”

Chemical Biodiversity and Bioactivities of Saponins in Echinodermata with an Emphasis on Sea Cucumbers (Holothuroidea)

“…Inhibition of Na + /K + -ATPase activity Kalinin et al (1989a) and Gorshkova et al (1999) Psolus eximius Kitagawa et al (1976) and Maltsev et al (1984Maltsev et al ( , 1985 Holotoxin A 1 Antiprotozoal, antitumor Kitagawa et al (1976) and Anisimov et al (1983) Holotoxin A 1 , cladoloside Neurotoxic, cytotoxic Yun et al (2018) Holotoxin A 1 Cytotoxic, antiproliferative activity Ishida et al 1993 andPopov et al 1994 Holotoxins A 1 , B 1 Inhibition of Na + /K + -ATPase activity Maltsev et al (1984) and Gorshkova et al (1989) Apostichoposide C…”