Current pharmaceutical design · 2026
Atorvastatin Enhances Doxorubicin Efficacy in Breast Cancer Through Convergent Disruption of Drug Efflux, Heat-Shock Response, and DNA Hypermethylation.
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Khafagy Salma Z, El-Baz Hatim A, Elshal Mohamed F
Аннотация
INTRODUCTION: Drug resistance limits the efficacy of anthracycline-based chemotherapy in breast cancer. This study investigated whether atorvastatin (ATR) enhances doxorubicin (DOX) activity by coordinating the disruption of multiple resistance pathways in MCF-7 cells.
METHODS: Cytotoxicity and drug interaction were quantified by MTT assay and Chou-Talalay analysis, respectively. Modulation of the cell death processes was assessed at the molecular level by evaluating Bcl-2 and Bax expression with qRT-PCR, while at the protein level, apoptosis was analyzed by Annexin V assay using flow cytometry. Global DNA methylation patterns were determined using 5-methylcytosine (5-mC)-targeted ELISA. Molecular docking simulations characterized ATR's binding interactions with P-glycoprotein (P-gp) and Heat Shock Factor-1 (HSF-1).
RESULTS: ATR and DOX produced consistent synergism (CI < 1) with a favorable dose-reduction index (DRI > 1) for DOX. The ATR-DOX combination also markedly shifted the Bcl-2/Bax balance toward apoptosis and increased apoptotic cells from 13.5% to 62% (~4.6-fold). The combination suppressed DOX-induced upregulation of HSP90 and HSP60 and significantly mitigated global DNA hypermethylation. In silico docking predicted favorable binding of ATR to P-glycoprotein (-10.24 kcal/mol) and Heat Shock Factor-1 DNA-binding domain (-6.69 kcal/mol), supporting potential modulation of drug efflux and stress-response pathways.
DISCUSSION: Collectively, atorvastatin enhances DOX cytotoxicity through integrated effects on efflux regulation, proteostasis, epigenetic regulation, and apoptotic priming.
CONCLUSION: Given its established clinical safety, atorvastatin represents a practical candidate for repurposing to improve anthracycline-based breast cancer therapy.
METHODS: Cytotoxicity and drug interaction were quantified by MTT assay and Chou-Talalay analysis, respectively. Modulation of the cell death processes was assessed at the molecular level by evaluating Bcl-2 and Bax expression with qRT-PCR, while at the protein level, apoptosis was analyzed by Annexin V assay using flow cytometry. Global DNA methylation patterns were determined using 5-methylcytosine (5-mC)-targeted ELISA. Molecular docking simulations characterized ATR's binding interactions with P-glycoprotein (P-gp) and Heat Shock Factor-1 (HSF-1).
RESULTS: ATR and DOX produced consistent synergism (CI < 1) with a favorable dose-reduction index (DRI > 1) for DOX. The ATR-DOX combination also markedly shifted the Bcl-2/Bax balance toward apoptosis and increased apoptotic cells from 13.5% to 62% (~4.6-fold). The combination suppressed DOX-induced upregulation of HSP90 and HSP60 and significantly mitigated global DNA hypermethylation. In silico docking predicted favorable binding of ATR to P-glycoprotein (-10.24 kcal/mol) and Heat Shock Factor-1 DNA-binding domain (-6.69 kcal/mol), supporting potential modulation of drug efflux and stress-response pathways.
DISCUSSION: Collectively, atorvastatin enhances DOX cytotoxicity through integrated effects on efflux regulation, proteostasis, epigenetic regulation, and apoptotic priming.
CONCLUSION: Given its established clinical safety, atorvastatin represents a practical candidate for repurposing to improve anthracycline-based breast cancer therapy.