Abstract

Metformin is one of the most widely prescribed antidiabetics for type 2 diabetes. A critical role of metformin against tumorigenesis has recently been implicated, although several studies also reported the lack of anticancer property of the antidiabetics. Given the controversies regarding the potential role of metformin against tumour progression, the effect of metformin against breast, cervical, and ovarian tumour cell lines was examined followed by in vivo assessment of metformin on tumour growth using xenograft breast cancer models. Significant inhibitory impact of metformin was observed in MCF-7, HeLa, and SKOV-3 cells, suggesting an antiproliferative property of metformin against breast, cervical, and ovarian tumour cells, respectively, with the breast tumour cells, MCF-7, being the most responsive. In vivo assessment was subsequently carried out, where mice with breast tumours were treated with metformin (20 mg/kg body weight) or sterile PBS solution for 15 consecutive days. No inhibition of breast tumour progression was detected. However, tumour necrosis was significantly increased in the metformin-treated group, accompanied by decreased capillary formation within the tumours. Thus, despite the lack of short-term benefit of metformin against tumour progression, a preventive role of metformin against breast cancer was implicated, which is at partially attributable to the attenuation of tumour angiogenesis.

Highlights

  • In recent years, epidemiological analyses have indicated a positive association between long-term diabetes and elevated risk of malignant neoplasms [1]

  • Given the controversies regarding the use of metformin as potential anticancer treatment, we examined the effect of metformin against selective tumour cell lines followed by in vivo assessment of metformin on tumour growth

  • The cytotoxicity of metformin was observed in all 3 cell types, with breast tumour cells being the most responsive, cautions need to be exercised when drawing conclusions from in vitro results since cultured tumour cells are morphologically and functionally different from native tumours

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Summary

Introduction

Epidemiological analyses have indicated a positive association between long-term diabetes and elevated risk of malignant neoplasms [1]. Patients with preexisting type 2 diabetes (T2D) present a higher risk of cancer development and cancer-related mortality. Given the potential causal relationship between T2D and cancer, multiple plasma glucose lowering agents have been selected to be tested for potential anticancer effects, with metformin showing the most promising result. Antiproliferative effects of metformin have been reported in multiple tumour cell lines via several molecular pathways, including the adenosine monophosphate kinase (AMPK) pathway, the insulin receptor cascade, and the AMPKindependent RagGTPase-dependent 3mTORC1 signalling network [1, 3]. Some studies observed no association between metformin and cancer-related mortality [5]. Results from a newly published epidemiological analysis reported no direct association between metformin and cancer outcome [6]. Given the controversies regarding the use of metformin as potential anticancer treatment, we examined the effect of metformin against selective tumour cell lines followed by in vivo assessment of metformin on tumour growth

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