Jaceidin Flavonoid Isolated from Chiliadenus montanus Attenuates Tumor Progression in Mice via VEGF Inhibition: In Vivo and In Silico Studies

Abstract

Phytochemical study of Chiliadenus montanus aerial parts afforded six compounds; Intermedeol (1), 5α-hydroperoxy-β-eudesmol (2), 5,7-dihydroxy-3,3',4'-trimethoxyflavone (3), 5,7,4'-trihydroxy-3,6,3'-trimethoxyflavone (jaceidin) (4), eudesm-11,13-ene-1β,4β,7α-triol (5) and 1β,4β,7β,11-tetrahydroxyeudesmane (6). These compounds were identified based on their NMR spectral data. The isolated compounds were tested for their cytotoxicity against liver cancer cell line (HepG2) and breast cancer cell line (MCF-7). Jaceidin flavonoid (4) exhibited the highest cytotoxic effect in vitro. Therefore, both of jaceidin and C. montanus extract were evaluated for their in vivo anti-tumor activity against Ehrlich's ascites carcinoma (EAC). Compared to control group, jaceidin and C. montanus extract decreased the tumor weight, improved the histological picture of tumor cells, lowered the levels of VEGF and ameliorate the oxidative stress. Molecular docking and in silico studies suggested that jaceidin was a selective inhibitor of VEGF-mediated angiogenesis with excellent membrane permeability and oral bioavailability.

Keywords: Chiliadenus montanus; Ehrlich’s ascites carcinoma; VEGF; anti-tumor; jaceidin.

Figure 1

Chemical structures of the isolated compounds.

Figure 2

Effect of Chiliadenus montanus extract and Jaceidin on weight on Ehrlich’s ascites carcinoma solid tumors growing in female mice. Data are expressed as the mean ± SD and analyzed using one-way ANOVA followed by Bonferroni’s post-hoc test. * compared to the tumor control group at p < 0.05.

Figure 3

Effect of Chiliadenus montanus extract and jaceidin on tumor giant cell count (a,d); mitotic picture (b,e) and necrotic area (c,f) on Ehrlich’s carcinoma solid tumors growing in female mice. Data are expressed as the mean ± SD and analyzed using one-way ANOVA followed by Bonferroni’s post-hoc test. * compared to the tumor control group at p < 0.001.

Figure 4

Effect of Chiliadenus montanus extract and jaceidin on GSH level (a) and MDA level (b) in Ehrlich’s carcinoma solid tumors growing in female mice. Data are expressed as the mean ± SD and analyzed using one-way ANOVA followed by Bonferroni’s post-hoc test. * compared to the tumor control group at p < 0.001.

Figure 5

Effect of Chiliadenus montanus extract and jaceidin on serum VEGF level in female mice bearing Ehrlich’s carcinoma solid tumors. VEGF: vascular endothelial growth factor. Data are expressed as the mean ± SD and analyzed using one-way ANOVA followed by Bonferroni’s post-hoc test. * compared to the tumor control group at p < 0.001.

Figure 6

(A) 3D-Binding mode of VGEFR-ligand, compound 4, compound 3, quercetin, and genistein in the catalytic domain of 3EWH. 2D-ligand interaction diagram of compound 4 (B), compound 3 (C), quercetin (D), and pazopanib (E).