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Abstract

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. 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, < 0.01) and apoptotic rate (38.6% vs. 16.2%, < 0.01). Moreover, MβCD reduced the expression of Flotillin-1, Caveolin-1, and P-gp in MDA-MB-231 cells. Importantly, sequential treatment achieved 73.6% tumor growth inhibition ( < 0.01 . 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.

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2026-04-06
2026-04-17

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Methyl-β-Cyclodextrin Enhances the Chemotherapeutic Efficacy of Paclitaxel in Breast Cancer Cells
Bentham Science Publishers ; https://doi.org/10.2174/0115680096430730260120060026
/content/journals/ccdt/10.2174/0115680096430730260120060026
/content/journals/ccdt/10.2174/0115680096430730260120060026
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  • Article Type:     Research Article
Keywords: sequential administration ; breast cancer ; lipid rafts ; flotillin-1 ; paclitaxel liposomes ; Methyl-β-cyclodextrin

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