Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Br J Pharmacol. 2019 Aug;176(15):2724-2735. doi: 10.1111/bph.14694. Epub 2019 Jun 26.
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.
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.
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.
An efficacious metformin dose for breast cancer varies among tumour subtypes based on cation transporter expression, which provides a useful guide for dose selection.
有大量报道称，一线抗糖尿病药物二甲双胍具有显著的抗癌作用。这种亲水性、阳离子药物需要阳离子转运体进入细胞，在细胞内激活其作用靶点 AMPK 信号通路。然而，二甲双胍治疗（用于抗糖尿病剂量）乳腺癌的临床结果并不明确。在低阳离子转运体表达的乳腺癌患者中，抗糖尿病剂量可能不足以使肿瘤对药物产生反应，这很可能是因为药物无法进入肿瘤细胞。我们推测阳离子转运体的表达和二甲双胍的剂量是其在乳腺癌中抗肿瘤疗效的关键决定因素。
我们比较了低阳离子转运体表达的 MCF-7 乳腺癌肿瘤和过表达有机阳离子转运体 3（OCT3-MCF7）的 MCF-7 肿瘤中二甲双胍的抗肿瘤疗效。我们在异种移植小鼠中研究了二甲双胍与标准治疗药物紫杉醇（用于雌激素受体阳性的 MCF-7 乳腺癌肿瘤）或卡铂（用于三阴性 MDA-MB-468 乳腺癌肿瘤）联合应用的剂量反应关系。
二甲双胍对阳离子转运体表达较高的肿瘤的疗效更好，这在 OCT3-MCF7 与 MCF-7 肿瘤和 MDA-MB-468 与 MCF-7 肿瘤的比较中得到了证实。在 MCF-7 肿瘤中，需要使用三倍剂量的二甲双胍才能达到与 MDA-MB-468 肿瘤相当的肿瘤内暴露水平，从而增强 MCF-7 肿瘤与 MDA-MB-468 肿瘤相比的标准治疗药物的抗肿瘤疗效。抗肿瘤疗效与肿瘤内 AMPK 激活和二甲双胍浓度相关。
根据阳离子转运体的表达，用于乳腺癌的有效二甲双胍剂量在肿瘤亚型之间存在差异，这为剂量选择提供了有用的指导。
