Abstract
The cytotoxic effects of thirteen triterpene glycosides from Holothuria scabra Jaeger and Cucumaria frondosa Gunnerus (Holothuroidea) against four human cell lines were detected and their cytotoxicity-structure relationships were established. The apoptosis-inducing activity of a more potent glycoside echinoside A (1) in HepG2 cells was further investigated by determining its effect on the morphology, mitochondrial transmembrane potential (Δψm) and mRNA expression levels of the apoptosis-related genes. The results showed that the number of glycosyl residues in sugar chains and the side chain of aglycone could affect their cytotoxicity towards tumor cells and selective cytotoxicity. 1 significantly inhibited cell viability and induced apoptosis in HepG2 cells. 1 also markedly decreased the Δψm and Bcl-2/Bax mRNA express ratio, and up-regulated the mRNA expression levels of Caspase-3, Caspase-8 and Caspase-9 in HepG2 cells. Therefore, 1 induced apoptosis in HepG2 cells through both intrinsic and extrinsic pathway. These findings could potentially promote the usage of these glycosides as leading compounds for developing new antitumor drugs.
Highlights
Conventional chemotherapeutics and targeted antineoplastic agents have been developed based on the simplistic notion that cancer constitutes a cell-autonomous genetic or epigenetic disease
These results suggested that the number of sugar residues, the presence of the 3-O-methyl group at the terminal monosaccharide units and sulfate group in the sugar side chains could affect the cytotoxic activities of sea cucumber triterpene glycosides
K562 cells were stronger than that of 7 and 8 by 2–5 times. These results suggested that the presence of hydroxyl and epoxy groups at the side chains of aglycone could decrease the cytotoxic activity towards tumor cells
Summary
Conventional chemotherapeutics and targeted antineoplastic agents have been developed based on the simplistic notion that cancer constitutes a cell-autonomous genetic or epigenetic disease. Triterpene aglycones exhibit 12, 16 and 17-hydroxy groups with a 9(11) or 7(8) double bond, of which the side chains diversify a lot by presenting double bond and oxidation to a certain extent [12,13] All of these made up quite a lot of holothurin analogs. The special and systematic study on structure-cytotoxicity and selective cytotoxicity of sea cucumber triterpene glycosides using a series of purified and structurally consecutive analogs may be useful for further modification and optimization in developing new anticancer drugs. Thirteen structurally consecutive triterpene glycosides (Figure 1 and Table 1) isolated from Holothuria scabra Jaeger (1–9) and Cucumaria frondosa Gunnerus (10–13) were evaluated for their cytotoxic activities against neoplastic and normal cell lines to assess the contribution of the structural characteristics on the bioactivities and to consider the structural factors essential for the fundamental antitumor effects and selective cytotoxicities of these glycosides. The chemical structures of a–i and S1–S5 see Figure 1
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