Asiatic acid exerts anticancer potential in human ovarian cancer cells via suppression of PI3K/Akt/mTOR signalling

Abstract

Context Asiatic acid, a triterpenoid compound extracted from the tropical medicinal plant Centella asiatica (Family: Apiaceae), has exhibited various biological activities. Objective This study was performed to investigate the cytotoxic effects of asiatic acid on human ovarian cancer cells. Materials and methods SKOV3 and OVCAR-3 ovarian cancer cells were exposed to different concentrations of asiatic acid (10-100 μg/mL) for 72 or 48 h. Cell viability, colony formation, cell cycle distribution, apoptotic response were examined. Involvement of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was tested. Results At the concentration of 40 μg/mL, asiatic acid caused about 50% reduction in the viability of ovarian cancer cells, but had little effect on the viability of normal human ovarian epithelial cells. Asiatic acid at 10 μg/mL reduced colony formation of ovarian cancer cells by 25-30%. Asiatic acid-treated cells showed a cell cycle arrest at the G0/G1 phase and 7- to 10-fold increase in apoptosis. The phosphorylation levels of PI3K, Akt and mTOR were remarkably lower in asiatic acid-treated cells. Overexpression of constitutively active Akt partially reversed the cytotoxic effects of asiatic acid, as evidenced by increased cell viability and colony formation. Furthermore, knockdown of Akt mimicked the growth-suppressive activity of asiatic acid. Discussion and conclusion These results provide first the evidence for the anticancer potential of asiatic acid in ovarian cancer cells, partially via inactivation of the PI3K/Akt/mTOR pathway. Asiatic acid may represent a potential therapeutic agent for ovarian cancer.

Asiatic Acid, Extracted from Centella asiatica and Induces Apoptosis Pathway through the Phosphorylation p38 Mitogen-Activated Protein Kinase in Cisplatin-Resistant Nasopharyngeal Carcinoma Cells

“…Our results in Figures 5 and 6 also indicate that caspase-3, -8, and -9 are upregulated in AA-induced apoptosis and that caspase-9 expression is mediated by the phosphorylation of p38 and ERK1/2 pathway in human NPC cell lines. Other research has indicated the anti-cancer activity of AA by Akt pathway [17,22], but our results didn't show it.…”

“…It has been proposed that Asiatic acid has various pharmacological activities such as anti-inflammatory and antioxidant, as well as the potent anti-hypertensive, neuro and cardio-protective, antimicrobial, and antitumor activities [5]. Many studies had proved the anti-cancer effects in vitro or in vivo of AA in breast cancer, ovary cancer, colon cancer, gastric cancer, cholangiocarcinoma, glioblastoma, lung cancer, lymphoma, and melanoma [6,[11][12][13][14][15][16][17][18]. Our study corresponds with these researches and revealed the anti-cancer effect of AA in both dose and time dependent manners in cisplatin-resistance NPC cell lines (Figure 1b).…”

Oleanolic acid from black raisins, Vitis vinifera with antioxidant and antiproliferative potentials on HCT 116 colon cancer cell line

“…The required concentration for the 50% inhibition (IC 50 ) of cells was 40 µg/mL (Figure 4).The similar class of pentacyclic triterpenoids like Asiatic acid (AA), betulinic acid (Bet A), boswellic acid (BA), glycyrrhizin, lupeol, ursolic acid (UA) and their derivatives were also reported previously to have a potent anticancer effect (Paduch, Kandefer-Szerszen, 2014). Asiatic acid (AA) caused about a 50% reduction in the viability of ovarian cancer cells SKOV3 and OVCAR-3 at the concentration of 40 μg/mL (Ren et al, 2016). Betulinic acid was active against breast cancer cell lines with an IC 50 value on MDA-MB-231 (21.9 µM) and MDA-MB-468 (46.0 µM) cell lines (Weber et al, 2014).…”

Asiatic Acid Inhibits OVX-Induced Osteoporosis and Osteoclastogenesis Via Regulating RANKL-Mediated NF-κb and Nfatc1 Signaling Pathways

“…It is reported that asiatic acid greatly inhibits endothelial hyperpermeability and suppresses the increased phosphorylation of IkB-a induced by TNF-a, contributing to the protection of human aortic endothelial cells from atherogenic stimuli (Fong et al, 2016). Asiatic acid also reduces the proliferation of human ovarian cancer cells by blocking the activation of the PI3K/Akt/mTOR pathway, as well as the proliferation of HepG2 cells by inhibiting the expression NDR1/2 kinase and enhancing the stability of p21WAF1/CIP1 protein (Chen et al, 2014;Ren et al, 2016). Furthermore, recent studies demonstrate that asiatic acid can attenuate neuroinflammation induced by various toxic agents via regulating Sirt1/NF-kB or NF-kB/STAT3/ERK signaling pathways (Park et al, 2017;Qian et al, 2018).…”