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. 2019 Dec 10;24(24):4520.
doi: 10.3390/molecules24244520.

Evodiamine Eliminates Colon Cancer Stem Cells via Suppressing Notch and Wnt Signaling

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Free PMC article

Evodiamine Eliminates Colon Cancer Stem Cells via Suppressing Notch and Wnt Signaling

Hyejin Kim et al. Molecules. .
Free PMC article

Abstract

Evodiamine, an alkaloid contained in traditional Asian herbal medicines that have been used for hundreds years, is interesting due to its cytotoxic effects against many cancers. We examined the effect of evodiamine on the cancer stem cell (CSC) population and the bulk cultured cancer cells (BCC) of colon cancers to examine the double targeting effect. We found that three colon cancer cell lines' BCC and CSC are effectively targeted by evodiamine. Evodiamine was able to suppress BCC proliferation and induce apoptosis of the cells captured in G2/M phase, as previously reported. However, evodiamine did not cause the accumulation of CSCs at a certain stage of the cell cycle, resulting in the elimination of stemness through an unknown mechanism. By analyzing the expression of 84 genes related to CSCs in two colon cancer cell lines' CSC, as well as performing further informatics analyses, and quantitative RT-PCR analyses of 24 CSC genes, we found that evodiamine suppressed the expression of the genes that control key signaling pathways of CSC, namely, WNT and NOTCH signaling, to lead CSC elimination. These results suggest that evodiamine should be further developed for targeting both BCCs and CSCs in colon cancers.

Keywords: WNT; cancer stem cell; colorectal cancer; evodiamine; notch.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Anti-proliferative/survival activity of evodiamine on bulk cultured cancer cells (BCC) and cancer stem cells (CSC) of colon cancer cell lines. (A) Relative cell numbers or CSC sphere (bigger than 100 μm in diameter) numbers after treated with evodiamine for 3 days (BCC) or 5 days (CSC). Average of six independent experiments were shown with error of means. BCC were maintained with 10% FBS or without FBS. X axis, evodiamine (μM); (B) Representative images of CSC spheres under microscope (scale bar represents 100 μm).
Figure 2
Figure 2
Cell cycle changed and cell death by evodiamine on BCC and CSC cells. (A) Cell cycle changes after evodiamine treatment for 48 h. G2/M accumulation in BCC is evident while no specific cell cycle blockage is seen in CSC but both induce cell death by evodiamine in a dose dependent manner. Average of four independent experiments were shown with error of means. (B) Scanning electron microscopy of CSCs showing apoptotic membranes in evodiamine treated CSC. Scale bar represents 100 μm, 10 μm, and 1 μm in 250×, 1000×, and 5000× images, respectively. ** p < 0.01 vs. control.
Figure 3
Figure 3
Evodiamine eliminated the cells with cancer stem cell activity in vitro and in vivo. (A) Limited dilution assay of the cells treated with evodiamine (200 nM for 24 h). (B) In vivo tumor growth activity of survived BCC cells after pretreated with evodiamine (1 μM for 24 h). n = 5 for each. Average with SEM. * p < 0.05; ** p < 0.01 vs. control.
Figure 4
Figure 4
Changes of cellular signaling by evodiamine in BCC and CSC. The cells treated with Evodiamine (200 nM and 500 nM) were treated to the bulk cultured or CSC enriched cells for 24 h and the cell lysates were applied to western blotting.
Figure 5
Figure 5
Cancer stem cell gene expression changes by evodiamine. (A) Cancer stem cells gene expression changes common between 48 h treated SW480 and 72 h treated HT29 CSC with mild (200 nM) evodiamine treatment. (B) The interaction of the commonly changes 17 genes is focused to NOTCH1 and WNT1.
Figure 6
Figure 6
Time dependent changes of CSC related cell signaling genes and marker genes expression in HT29. The CSC enriched cultured cells were treated with evodiamine for 48 h or 72 h and the mRNA expressions were tested with quantitative RT-PCR. Only Notch1, LRP5, Jagged, CD133 and SCD1 showed similar expression changes in time dependent manner. * p < 0.05; ** p < 0.01; *** p < 0.001 vs. each controls.

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