Methyl-β-Cyclodextrin Enhances the Chemotherapeutic Efficacy ofPaclitaxel in Breast Cancer Cells

BACKGROUND: Chemoresistance, a long-standing clinical challenge in breast cancer treatment, continues to affect chemotherapy outcomes. Cholesterol-enriched lipid rafts are increasingly recognized as key mediators of drug efflux, primarily via transporters like P-glycoprotein (P-gp). Therefore, targeting lipid rafts as a viable treatment strategy to restore cancer sensitivity to chemotherapeutics. Our study aims to evaluate whether methyl-β-cyclodextrin (MβCD), a well-characterized lipid raft disruptor, can enhance the antitumor efficacy of paclitaxel liposomes (PTX-LPs) in preclinical breast cancer models, with a particular focus on triple-negative breast cancer subtypes. METHODS: The sequential effects of paclitaxel liposomes (PTX-LPs) and MβCD were evaluated in vitro in MDA-MB-231 cells with a 1-hour dosing interval. Intracellular paclitaxel retention, apoptotic rate, and the expression of Flotillin-1, Caveolin-1, and P-gp were quantified by HPLC, flow cytometry, and Western blotting. In vivo therapeutic effects were further assessed in tumor-bearing xenograft models following sequential administration with a 5-hour interval. RESULTS: Flotillin-1 was significantly overexpressed across breast cancer subtypes. Sequential PTX-LPs and MβCD treatment significantly increased intracellular paclitaxel retention (3-fold at 48 h vs. PTX-LPs alone, p < 0.01) and apoptotic rate (38.6% vs. 16.2%, p < 0.01). Moreover, MβCD reduced the expression of Flotillin-1, Caveolin-1, and P-gp in MDA-MB231 cells. Importantly, sequential treatment achieved 73.6% tumor growth inhibition in vivo (p < 0.01 vs. PTX-LPs alone). DISCUSSION: Breast cancer chemoresistance is closely associated with lipid rafts. Here, we demonstrate that sequential treatment with MβCD and PTX-LPs disrupts lipid rafts, suppresses efflux transporter activity, enhances intracellular paclitaxel retention, and potentiates paclitaxel efficacy in MDA-MB-231 cells. However, the long-term safety of MβCD and its applicability to other breast cancer subtypes remain to be further investigated. CONCLUSION: Sequential therapy with MβCD and PTX-LPs enhances the chemotherapeutic efficacy of PTX-LPs in breast cancer. This effect is mediated by the inhibition of drug efflux through the disruption of lipid raft integrity. This strategy provides a novel approach to overcoming chemoresistance.