Betulinic Acid Suppresses Ovarian Cancer Cell Proliferation through Induction of Apoptosis

Abstract

Ovarian cancer is one of the leading causes of cancer deaths worldwide in women, and the most malignant cancer among the different gynecological cancers. In this study, we explored potentially anticancer compounds from Cornus walteri (Cornaceae), the MeOH extract of which has been reported to show considerable cytotoxicity against several cancer cell lines. Phytochemical investigations of the MeOH extract of the stem and stem bark of C. walteri by extensive application of chromatographic techniques resulted in the isolation of 14 compounds (1–14). The isolated compounds were evaluated for inhibitory effects on the viability of A2780 human ovarian carcinoma cells and the underlying molecular mechanisms were investigated. An 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to assess the anticancer effects of compounds 1–14 on A2780 cells, which showed that compound 11 (betulinic acid) reduced the viability of these cells in a concentration-dependent manner and had an half maximal (50%) inhibitory concentration (IC50) of 44.47 μM at 24 h. Nuclear staining and image-based cytometric assay were carried out to detect the induction of apoptosis by betulinic acid. Betulinic acid significantly increased the condensation of nuclei and the percentage of apoptotic cells in a concentration-dependent manner in A2780 cells. Western blot analysis was performed to investigate the underlying mechanism of apoptosis. The results indicated that the expression levels of cleaved caspase-8, -3, -9, and Bax were increased in A2780 cells treated with betulinic acid, whereas those of Bcl-2 were decreased. Thus, we provide the experimental evidence that betulinic acid can induce apoptosis in A2780 cells through both mitochondria-dependent and -independent pathways and suggest the potential use of betulinic acid in the development of novel chemotherapeutics for ovarian cancer therapy.

Betulinic acid triggers apoptosis and inhibits migration and invasion of gastric cancer cells by impairing EMT progress

“…[24][25][26] Furthermore, BA has shown tumorigenesis inhibition in many kinds of cancers, including lung, colon, breast, prostate and pancreatic cancer. [27][28][29][30] In the present study, our results showed that BA distinctly triggered apoptosis and suppressed the proliferation, migration and invasion of GC cells in vitro. The in vivo anti-tumour efficacy was consistent with that reported in vitro studies.…”

“…32 It is widely reported that BA is cytotoxic to various types of human cancer cells. [28][29][30] In the present study, we assessed the antitumour effect of BA on human GC cells in vitro and in vivo. nalling pathway and inhibits hepatocellular carcinoma.…”

(-)-Leucophyllone, a Tirucallane Triterpenoid from Cornus walteri, Enhances Insulin Secretion in INS-1 Cells

“…Plants 2021, 10, 431 2 of 8 acid on A2780 human ovarian cancer cells and the renoprotective effect of benzyl salicylate on cisplatin-induced damage in LLC-PK1 kidney proximal tubule cells have been explored and evaluated in our previous studies [16,17]. In the present study, we focused on (-)-leucophyllone, a tirucallane triterpenoid isolated from the further phytochemical investigation of the MeOH extract from C. walteri.…”

“…Our previous phytochemical analysis on C. walteri led to the isolation of triterpenoids, including betulinic acid methyl ester, lupenone, lupeol, betulinic acid, methyl 3-O-acetyl betulinate, and sterols such as 6β-hydroxysitostenone, 5α-stigmast-3,6-dione, sitostenone, 3β-sitostanol, and 6α-hydroxy-β-sitostenone [16,17]. Among them, the anticancer effect of betulinic acid on A2780 human ovarian cancer cells and the renoprotective effect of benzyl Plants 2021, 10, 431 2 of 7 salicylate on cisplatin-induced damage in LLC-PK1 kidney proximal tubule cells have been explored and evaluated in our previous studies [16,17]. In the present study, we focused on (-)-leucophyllone, a tirucallane triterpenoid isolated from the further phytochemical investigation of the MeOH extract from C. walteri.…”

Identification of Bioactive Natural Product from the Stems and Stem Barks of Cornus walteri: Benzyl Salicylate Shows Potential Anti-Inflammatory Activity in Lipopolysaccharide-Stimulated RAW 264.7 Macrophages

“…In our previous chemical investigation of C. walteri , we identified triterpenoids and δ-valerolactones, which showed cytotoxicity against several human cancer cell lines, using bioassay-guided fractionation of the methanol extract of C. walteri [ 16 , 17 , 18 , 19 ]. In particular, we found that betulinic acid, a triterpenoid, reduced the viability of A2780 human ovarian carcinoma cells and induced apoptotic cell death through both extrinsic and intrinsic apoptosis pathway [ 19 ]. Furthermore, we identified new tirucallane triterpenoids (cornusalterins N-P) in C. walteri , along with bioactive tirucallane triterpenoids that control adipocyte and osteoblast differentiation [ 20 ].…”