Anticancer effect of involucrasin A on colorectal cancer cells by modulating the Akt/MDM2/p53 pathway

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer mortality worldwide; however, there is still a lack of effective clinical anti-CRC agents. Naturally-occurring compounds have been considered a potentially valuable source of new antitumorigenic agents. Involucrasin A, a novel natural molecule, was isolated from Shuteria involucrata (Wall.) Wight & Arn by our team. In the present study, the anticancer activity of involucrasin A in HCT-116 CRC cells was evaluated. Firstly, the anti-proliferative effect of involucrasin A on HCT-116 cells was analyzed by sulforhodamine B and colony formation assays. The results revealed that involucrasin A exhibited a potent inhibitory effect on HCT-116 CRC cell proliferation in vitro. Subsequently, flow cytometry and western blotting indicated that involucrasin A induced apoptosis and upregulated the expression levels of apoptosis-related proteins, such as cleaved-caspase 6 and cleaved-caspase 9, in a dose-dependent manner. Mechanistically, involucrasin A significantly inhibited the phosphorylation of Akt and murine double minute 2 homologue (MDM2), which resulted in increased intracellular levels of p53. This was reversed by exogenous expression of the constitutively active form of Akt. Similarly, either knocking out p53 or knocking down Bax abrogated involucrasin A-induced proliferation inhibition and apoptosis. Together, the present study indicated that involucrasin A exerts antitumorigenic activities via modulating the Akt/MDM2/p53 pathway in HCT-116 CRC cells, and it is worthy of further exploration in preclinical and clinical trials.

Involucrasin B Inhibits the Proliferation of Caco-2 Cells by Regulating the TGFβ/SMAD2-3-4 Pathway

“…Both compounds exhibited significant inhibitory effects on CRC cells, although their specific inhibitory mechanisms differed. Involucrasin A induced cell death in CRC cells by modulating the Akt/MDM2/P53 pathway [8], while involucrasin B, as investigated in this study, suppressed CRC cell proliferation by regulating the TGFβ/SMAD2-3-4 pathway. Comparative and repetitive analysis of the nuclear magnetic resonance spectra revealed that the ~1H and ~(13) C NMR spectra of involucrasin B were highly similar to those of involucrasin A, except for the absence of the methoxy signal in involucrasin B [13].…”

“…However, despite treatment advancements, advanced CRC still exhibits high mortality rates [7]. Studies suggest that while screening has reduced early morbidity, there has been an increase in the occurrence and fatality of advanced CRC in recent years [6,8]. The chemotherapy limitations in current CRC management include systemic toxicity, low tumor specificity, and acquired drug resistance [8].…”

“…Studies suggest that while screening has reduced early morbidity, there has been an increase in the occurrence and fatality of advanced CRC in recent years [6,8]. The chemotherapy limitations in current CRC management include systemic toxicity, low tumor specificity, and acquired drug resistance [8]. Therefore, it is crucial to introduce new compounds that are highly efficient, safe, stable, and effective for the clinical management of CRC.…”

“…About 80% of approved anticancer drugs originate from natural compounds or their derivatives, highlighting natural products as the primary source of new antineoplastic medications. Flavonoids, characterized by a 2-phenyl chromone structure, offer various biological benefits, such as cardiovascular protection and antibacterial, antiviral, antitumor, antioxidant, anti-inflammatory, antihypertensive, hypolipidemic, immune-boosting, antitussive, and spasmolytic activities [8,9]. Numerous flavonoids have exhibited antitumor activities on CRC cells [10][11][12].…”

“…Wei et al evaluated the anticancer activity of involucrasin A in HCT-116 CRC cells. Their findings revealed that involucrasin A primarily exerts its anti-tumor effects by modulating the Akt/MDM2/P53 pathway [8]. While the anti-tumor activities and mechanism of action of involucrasin A on CRC cells have been recently investigated, the impact of involucrasin B remains unclear.…”