Abstract
Colorectal cancer (CRC) represents the third leading cause of death among cancer patients below the age of 50, necessitating improved treatment and prevention initiatives. A crude methanol extract from the wood pulp of Artocarpus heterophyllus was found to be the most bioactive among multiple others, and an enriched extract containing 84% (w/v) artocarpin (determined by HPLC–MS–DAD) was prepared. The enriched extract irreversibly inhibited the activity of human cytochrome P450 CYP2C9, an enzyme previously shown to be overexpressed in CRC models. In vitro evaluations on heterologously expressed microsomes, revealed irreversible inhibitory kinetics with an IC50 value of 0.46 µg/mL. Time- and concentration-dependent cytotoxicity was observed on human cancerous HCT116 cells with an IC50 value of 4.23 mg/L in 72 h. We then employed the azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-induced model in C57BL/6 mice, which revealed that the enriched extract suppressed tumor multiplicity, reduced the protein expression of proliferating cell nuclear antigen, and attenuated the gene expression of proinflammatory cytokines (Il-6 and Ifn-γ) and protumorigenic markers (Pcna, Axin2, Vegf, and Myc). The extract significantly (p = 0.03) attenuated (threefold) the gene expression of murine Cyp2c37, an enzyme homologous to the human CYP2C9 enzyme. These promising chemopreventive, cytotoxic, anticancer and anti-inflammatory responses, combined with an absence of toxicity, validate further evaluation of A. heterophyllus extract as a therapeutic agent.
Highlights
Colorectal cancer (CRC) represents the third leading cause of death among cancer patients below the age of 50, necessitating improved treatment and prevention initiatives
Given the putative role of CYP2C enzymes in the pathogenesis of CRC in humans and mice 13, we evaluated the inhibitory potential of the A. heterophyllus extract on the activities of human CYP2C9 and 2C19 enzymes
Using numerous in vitro and in vivo tools, we demonstrate the promising application of a prepared botanical wood extract (A. heterophyllus extract, 84% (w/v) artocarpin) in the reduction of tumor multiplicity, proinflammatory biomarkers, and gene expression and activities of cytochrome P450 2C enzymes, indicative of potential chemoprevention
Summary
Colorectal cancer (CRC) represents the third leading cause of death among cancer patients below the age of 50, necessitating improved treatment and prevention initiatives. The extract significantly (p = 0.03) attenuated (threefold) the gene expression of murine Cyp2c37, an enzyme homologous to the human CYP2C9 enzyme These promising chemopreventive, cytotoxic, anticancer and anti-inflammatory responses, combined with an absence of toxicity, validate further evaluation of A. heterophyllus extract as a therapeutic agent. Following numerous in vitro evaluations using heterologously expressed human CYP enzymes, as well as human cancer cell lines, we used the AOM/DSS model, a chemically induced colitis-associated cancer (CAC) mouse model employing azoxymethane (AOM) and dextran sulfate sodium (DSS) carcinogens, which mimics a form of inflammatory colorectal cancer in humans, to assess the impact of the A. heterophyllus extract on colon tumor development[19,20]
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