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Mar Drugs
2024 Jun 26;227:. doi: 10.3390/md22070294.
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Sulfated Polyhydroxysteroid Glycosides from the Sea of Okhotsk Starfish Henricia leviuscula spiculifera and Potential Mechanisms for Their Observed Anti-Cancer Activity against Several Types of Human Cancer Cells.
Kicha AA
,
Tolkanov DK
,
Malyarenko TV
,
Malyarenko OS
,
Kuzmich AS
,
Kalinovsky AI
,
Popov RS
,
Stonik VA
,
Ivanchina NV
,
Dmitrenok PS
.
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Three new monosulfated polyhydroxysteroid glycosides, spiculiferosides A (1), B (2), and C (3), along with new related unsulfated monoglycoside, spiculiferoside D (4), were isolated from an ethanolic extract of the starfish Henricia leviuscula spiculifera collected in the Sea of Okhotsk. Compounds 1-3 contain two carbohydrate moieties, one of which is attached to C-3 of the steroid tetracyclic core, whereas another is located at C-24 of the side chain of aglycon. Two glycosides (2, 3) are biosides, and one glycoside (1), unlike them, includes three monosaccharide residues. Such type triosides are a rare group of polar steroids of sea stars. In addition, the 5-substituted 3-OSO3-α-L-Araf unit was found in steroid glycosides from starfish for the first time. Cell viability analysis showed that 1-3 (at concentrations up to 100 μM) had negligible cytotoxicity against human embryonic kidney HEK293, melanoma SK-MEL-28, breast cancer MDA-MB-231, and colorectal carcinoma HCT 116 cells. These compounds significantly inhibited proliferation and colony formation in HCT 116 cells at non-toxic concentrations, with compound 3 having the greatest effect. Compound 3 exerted anti-proliferative effects on HCT 116 cells through the induction of dose-dependent cell cycle arrest at the G2/M phase, regulation of expression of cell cycle proteins CDK2, CDK4, cyclin D1, p21, and inhibition of phosphorylation of protein kinases c-Raf, MEK1/2, ERK1/2 of the MAPK/ERK1/2 pathway.
Figure 1. The chemical structures of spiculiferosides A (1), B (2), C (3), and D (4).
Figure 2. 1H-1H COSY and main HMBC correlations of steroid glycosides 1–4.
Figure 3. Main ROESY correlations for steroid glycosides 1–4.
Figure 4. The cytotoxic activity of compounds 1, 2, and 3 against human normal and cancer cells. (A) Human embryonic kidney HEK293, (B) melanoma SK-MEL-28, (C) breast cancer MDA-MB-231, and (D) colorectal carcinoma HCT 116 cells were treated with 1, 2, and 3 (1, 10, 50, and 100 µM) for 24 h. MTS assay was used to evaluate cytotoxicity of compounds. IC50—the concentration at which the compounds exert half of their maximal inhibitory effect on cell viability. The data results are presented as mean ± SD for triplicate experiments. A one-way ANOVA and Tukey’s HSD test for multiple comparisons indicated the statistical significance (* p < 0.05).
Figure 5. The effect of compounds 1, 2, and 3 on the proliferation of human colorectal carcinoma cells HCT 116. HCT 116 cells were treated with compounds 1 (A), 2 (B), and 3 (C) at concentrations of 1, 10, 50, and 100 µM for 24, 48, and 72 h. MTS assay was used to evaluate anti-proliferative activities of compounds. A one-way ANOVA and Tukey’s HSD test for multiple comparisons indicated the statistical significance (* p < 0.05; ** p < 0.01; *** p < 0.001).
Figure 6. The effect of compounds 1, 2, and 3 on the colony formation in human colorectal carcinoma cells HCT 116. HCT 116 cells were treated by 1 (A), 2 (B), and 3 (C) at concentrations of 10, 20, and 40 µM in soft agar. The number of colonies was counted under a microscope (at a total magnification of 40×) using the ImageJ software version 1.50i bundled with 64-bit Java 1.6.0_24 (“NIH”, Bethesda, MD, USA). Results are presented as mean ± standard deviation (SD). A one-way ANOVA and Tukey’s HSD test for multiple comparisons indicated the statistical significance (* p < 0.05, ** p < 0.01, *** p < 0.001).
Figure 7. The effect of compound 3 on cell cycle regulation and the expression of cell cycle markers and MAPK kinases in human colorectal carcinoma cells HCT 116. (A,B) HCT 116 cells were treated with 3 at 10, 20, and 40 µM for 72 h. The percentage of cells in G0/G1, S, and G2/M phases was determined using a Muse cell analyzer. Histograms from a representative experiment show the effect of 3 on cell cycle profile. (C) The regulation of expression of cell cycle markers, MAPK, and β-actin by 3 (10, 20, and 40 µM) after 72 h of treatment of HCT 116 cells. (D) Relative band density was measured using the Quantity One 1D analysis software version 4.6.7. Band density was normalized to β-actin total level. Results are presented as mean ± standard deviation (SD). A one-way ANOVA and Tukey’s HSD test for multiple comparisons indicated the statistical significance (* p < 0.05; ** p < 0.01; *** p < 0.001).
