Crocetin Halts Tumorigenesis in Metastatic Breast Cancer via Disrupting CYP2J2/EET Axis
Abstract
CYP2J2 catalyzes the conversion of arachidonic acid into epoxyeicosatrienoic acids (EET), which have gained significant attention due to their oncogenic properties. Differential overexpression of CYP2J2 in tumors results in increased EET production. The role of EET in tumorigenesis is quite clear, but inhibition of CYP2J2 on EET formation with its molecular target is poorly understood. Research is ongoing to identify CYP2J2 inhibitors and the role of the CYP2J2/EET axis in halting tumorigenesis. In these contexts, we aimed to address the same through in silico, in vitro, and in vivo approaches using crocetin, a phyto-based druggable molecule. In vitro mechanistic investigations using human liver microsomes (HLM) indicate that crocetin could act as a specific and reversible CYP2J2 inhibitor. In silico molecular docking analysis and molecular dynamics (MD) simulation explicate strong and stable interactions between crocetin and active site of human CYP2J2. In vivo investigations in BALB/c mice reveal that crocetin could enhance the plasma exposure of rivaroxaban (CYP2J2 substrate) by delaying metabolism and attenuating CYP2J2 protein expression in the liver tissues. Additionally, in vitro studies using HLM and mouse liver microsomes (MLM) suggest that crocetin could substantially hinder EET formation. Thereafter, crocetin showcases its antitumor effect in the mouse model of breast cancer involving downregulation of CYP2J2 expression and impediment of EET formation in the tumor…
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