Efficacious dose of metformin for breast cancer therapy is determined by cation transporter expression in tumours

• Published in: British journal of pharmacology 2019-08, Vol.176 (15), p.2724-2735
• Main Authors: Cai, Hao, Everett, Ruth S., Thakker, Dhiren R.
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Antidiabetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer therapies; Carboplatin; Carboplatin - therapeutic use; Cell Line, Tumor; Diabetes mellitus; Drug dosages; Drug Synergism; Exposure; Female; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Intracellular signalling; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - pathology; Metformin; Metformin - pharmacology; Metformin - therapeutic use; Mice, Nude; Oct-4 protein; Organic Cation Transport Proteins - genetics; Organic cation transporter; Paclitaxel; Paclitaxel - therapeutic use; Research Paper; Research Papers; Signal transduction; Tumor Burden - drug effects; Tumors; Xenografts
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14694

Background and Purpose It has been extensively reported that the leading anti‐diabetic drug, metformin, exerts significant anticancer effects. This hydrophilic, cationic drug requires cation transporters for cellular entry where it activates its intracellular target, the AMPK signalling pathway. However, clinical results on metformin therapy (used at antidiabetic doses) for breast cancer are ambiguous. It is likely that the antidiabetic dose is inadequate in patients that have breast tumours with low cation transporter expression, resulting in non‐responsiveness to the drug. We postulate that cation transporter expression and metformin dose are key determinants in its antitumour efficacy in breast cancer. Experimental Approach Antitumour efficacy of metformin was compared between low cation transporter‐expressing MCF‐7 breast tumours and MCF‐7 tumours overexpressing organic cation transporter 3 (OCT3‐MCF7). A dose–response relationship of metformin in combination with standard‐of‐care paclitaxel (for oestrogen receptor‐positive MCF‐7 breast tumours) or carboplatin (for triple‐negative MDA‐MB‐468 breast tumours) was investigated in xenograft mice. Key Results Metformin had greater efficacy against tumours with higher cation transporter expression, as observed in OCT3‐MCF7 versus MCF‐7 tumours and MDA‐MB‐468 versus MCF‐7 tumours. In MCF‐7 tumours, a threefold higher metformin dose was required to achieve intratumoural exposure that was comparable to exposure in MDA‐MB‐468 tumours and enhance antitumour efficacy of standard‐of‐care in MCF‐7 tumours versus MDA‐MB‐468 tumours. Antitumour efficacy correlated with intratumoural AMPK activation and metformin concentration. Conclusions and Implications An efficacious metformin dose for breast cancer varies among tumour subtypes based on cation transporter expression, which provides a useful guide for dose selection.