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. 2024 Aug 26;29(17):4026.
doi: 10.3390/molecules29174026.

Effects of Isoxazolyl Steroids on Key Genes of Sonic Hedgehog Cascade Expression in Tumor Cells

Affiliations

Effects of Isoxazolyl Steroids on Key Genes of Sonic Hedgehog Cascade Expression in Tumor Cells

Anna Aleksandrova et al. Molecules. .

Abstract

Activation of the Hedgehog (Hh) signaling pathway is often associated with the progression of various types of cancer. The purpose of study was to search for inhibitors of the Hh signaling pathway among eight compounds belonging to the group of isoxazolyl steroids. The evaluation of the effectiveness of the compounds was based on the analysis of their cytotoxicity, effect on the cell cycle, on the expression of key Hh-signaling-pathway genes (Ptch1, Smo, and Gli1) and putative target genes MMP-2 and MMP-9. Four compounds with the most pronounced cytotoxic effect were identified: compounds 1, 2 (HeLa cells) and 3, 4 (A549 cells). Compounds 1 and 2 significantly reduced the expression of the Ptch1, Smo, Gli1 genes, but had the opposite effect on MMP-2 gene expression: Compound 1 increased it, and compound 2 decreased it. Compounds 3 and 4 did not have a noticeable inhibitory effect on the expression of the Shh pathway receptors, but significantly inhibited MMP-2 and MMP-9 expression. Thus, it was shown that inhibition of the Shh signaling pathway by isoxazolyl steroids can have the opposite effect on MMPs gene expression, which is what should be taken into account in further studies of these compounds as therapeutic agents.

Keywords: Hh receptors; MMP; cancer cell proliferation; isoxazoles; steroids.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The binding modes of cyclopamine (A), 1 (B), 2 (C), 3 (D), 4 (E), 5 (F), 6 (G), 7 (H), and 8 (I). The yellow dotted lines are hydrogen bonds.
Figure 2
Figure 2
The effect of isoxazolyl steroids on the viability of HeLa cells (a) and A549 cells (b) during incubation for 48 h in DMEM medium with 10% FBS.
Figure 3
Figure 3
Flow cytometric analysis of DNA content in HeLa cells. (a) Intact HeLa cells; (b) HeLa cells incubated for 48 h with compound 1; (c) HeLa cells incubated for 48 h with compound 2. SubG0/G1 peaks on histograms indicate apoptotic cells; G0/G1, S, and G2/M—phases of cell cycle.
Figure 4
Figure 4
Flow cytometric analysis of DNA content in HeLa cells. (a) Intact A549 cells; (b) A549 cells incubated for 48 h with compound 3; (c) A549 cells incubated for 48 h with compound 4. SubG0/G1 peaks on histograms indicate apoptotic cells; G0/G1, S, and G2/M—phases of cell cycle.
Figure 5
Figure 5
Effect of isoxazolyl steroids 1 and 2 on expression of Hh pathway receptors genes in HeLa cell line. ** p < 0.05.
Figure 6
Figure 6
Effect of isoxazolyl steroids 1 and 2 on expression of MMP-2 and MMP-9 genes in HeLa cell line. ** p < 0.05.
Figure 7
Figure 7
Effect of isoxazolyl steroids 3 and 4 on expression of Hh pathway receptors genes in A549 cell line.
Figure 8
Figure 8
Effect of isoxazolyl steroids 3 and 4 on expression of MMP-2 and MMP-9 genes in A549 cells line. ** p < 0.05.
Figure 9
Figure 9
The effect of isoxazolyl steroids 1 and 2 on the viability of MCF-7 cells during incubation for 48 h in DMEM medium with 10% FBS.

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