β-Sitosterol Reverses Multidrug Resistance via BCRP Suppression by Inhibiting the p53-MDM2 Interaction in Colorectal Cancer

Phytosterols are widely present in vegetable oils, nuts, cereal products, fruits, and berries. Phytosterol-induced treatment sensitivity has recently shed light on alleviating multidrug resistance in cancer therapy. Here, we demonstrated that beta-sitosterol, the most common dietary phytosterol, recovers oxaliplatin (OXA) sensitivity in drug-resistant colorectal cancer (CRC) cells by inhibiting breast cancer resistance protein (BCRP) expression. We further showed evidence that beta-sitosterol could activate p53 by disrupting the p53-MDM2 interaction, leading to an increase in p53 translocation to the nucleus and silencing the nuclear factor-kappa B (NF-kappa B) pathway, which is necessary for BCRP expression. Finally, we suggested that the combination of OXA and beta-sitosterol has a synergistic tumor suppression effect in vivo using a xenograft mouse model. These results revealed that beta-sitosterol is able to mediate the p53/NF-kappa B/BCRP signaling axis to regulate the response of CRC to chemotherapy. The combined application of beta-sitosterol and OXA can be a potential way to improve CRC treatment.