Enhancement of Doxorubicin Efficacy by Bacopaside II in Triple-Negative Breast Cancer Cells

• DOI: 10.20944/preprints202412.0358.v1
• Publication Date: 2024-12-05T06:38:46Z
• Authors: Sima Kianpour Rad; Kenny K. L. Yeo; Runhao Li; Fangmeinuo Wu; Saifei Liu; Saeed Nourmohammadi; William M. Murphy; Yoko Tomita; Timothy J. Price; Wendy V. Ingman; Amanda R. Townsend; Eric Smith
• Keywords: molecular subtypes; <i>Bacopa monnieri</i>; triple-negative breast cancer; chemotherapy; doxorubicin; Microbiology; QR1-502; Article; bacopaside II

Background: Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options and high drug resistance. Doxorubicin is commonly used for TNBC, but variable sensitivity across subtypes, resistance development and toxicity limit its effi-cacy. Bacopaside II, a saponin compound, has shown anti-cancer potential. This study assesses the effects of doxorubicin and bacopaside II, individually and combined, across TNBC subtypes to explore mechanisms of drug sensitivity, resistance, and enhanced efficacy. Methods: The growth-inhibitory effects of doxorubicin and bacopaside II in four TNBC cell lines representing different TNBC subtypes was evaluated. IC50 values were determined using dose-response as-says, and doxorubicin accumulation was measured via spectral flow cytometry. ATP-binding cassette (ABC) transporter expression (ABCB1, ABCC1, ABCC3, ABCG2) was analyzed for cor-relations with drug sensitivity. In silico docking assessed binding affinity of bacopaside II to ABC transporters. A 3D culture model simulated drug-resistant TNBC, and combination effects were evaluated with live-cell imaging. Results: Doxorubicin IC50 values varied significantly across cell lines, with sensitivity correlating to intracellular accumulation. Bacopaside II inhibit-ed growth across TNBC subtypes, inducing apoptosis in sensitive cells and necrosis in resistant cells. Bacopaside II increased doxorubicin accumulation, independent of P-glycoprotein (ABCB1), possibly through interactions with other ABC transporters. In drug-resistant 3D cultures, ba-copaside II maintained efficacy and enhanced doxorubicin accumulation, counteracting ABC transporter-mediated resistance. The doxorubicin and bacopaside II combination showed syner-gistic growth inhibition. Conclusions: Bacopaside II enhances doxorubicin efficacy in TNBC by increasing drug accumulation and overcoming ABC transporter-mediated resistance, suggesting its potential as an adjuvant in TNBC treatment. These findings support further investigation of bacopaside II, particularly for resistant TNBC subtypes.