Crocetin Impairs the Cytochrome P450 Epoxygenase Pathway toward Potentiating the Therapeutic Efficacy of Paclitaxel in Metastatic Breast Cancer

Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer owing to its aggressive nature and limited treatment strategies. Despite significant advancements in cancer research, targeted therapeutic interventions to mitigate TNBC remain limited. Paclitaxel is heavily relied on as a frontline chemotherapy drug for managing breast cancer, but its treatment is often associated with emerging resistance and the onset of severe adverse effects. In the quest to identify an appropriate combination therapy with a low dose of paclitaxel, we explored crocetin using a highly aggressive mouse carcinoma model of breast cancer. The findings demonstrate that crocetin enhanced the therapeutic efficacy of paclitaxel by reducing the tumor burden and limiting the metastatic lung nodule count. Crocetin, in combination with paclitaxel, markedly altered the expression of key epithelial-mesenchymal transition (EMT) markers and substantially upregulated the pro-apoptotic markers. Concurrent treatment of crocetin and paclitaxel suppressed CYP2J2 expression and decreased epoxyeicosatrienoic acid (EET) levels in the tumor tissue. Dysregulated proteins from untargeted proteomics data indicate that crocetin boosted the antimetastatic efficacy of paclitaxel, possibly via modulating extracellular matrix organization. In combination with paclitaxel, crocetin exerted preventive effects by normalizing the cancer-linked WBC count. Devoid of any observed pharmacokinetic effect of crocetin on paclitaxel, overall results dictate that crocetin has significant potential to boost the efficacy of paclitaxel with a possibly crucial contribution from the CYP2J2/EET axis, leading to restricting tumorigenesis. Thus, elucidating the putative molecular signaling pathway is suggested for this promising combination therapy under the frame of targeted therapeutics to combat TNBC.