Abstract
Metformin is a metabolic disruptor, and its efficacy and effects on metabolic profiles under different oxygen and nutrient conditions remain unclear. Therefore, the present study examined the effects of metformin on cell growth, the metabolic activities and consumption of glucose, glutamine, and pyruvate, and the intracellular ratio of nicotinamide adenine dinucleotide (NAD+) and reduced nicotinamide adenine dinucleotide (NADH) under normoxic (21% O2) and hypoxic (1% O2) conditions. The efficacy of metformin with nutrient removal from culture media was also investigated. The results obtained show that the efficacy of metformin was closely associated with cell types and environmental factors. Acute exposure to metformin had no effect on lactate production from glucose, glutamine, or pyruvate, whereas long-term exposure to metformin increased the consumption of glucose and pyruvate and the production of lactate in the culture media of HeLa and HaCaT cells as well as the metabolic activity of glucose. The NAD+/NADH ratio decreased during growth with metformin regardless of its efficacy. Furthermore, the inhibitory effects of metformin were enhanced in all cell lines following the removal of glucose or pyruvate from culture media. Collectively, the present results reveal that metformin efficacy may be regulated by oxygen conditions and nutrient availability, and indicate the potential of the metabolic switch induced by metformin as combinational therapy.
Highlights
Most tumors are rich in hypoxic and nutrient-insufficient regions generally because of the high rate of proliferation of their cells and poor vascularization
To investigate the anti-cancer effects of metformin under different oxygen conditions, cells were cultured with 0–10 mM metformin under normoxic (21% O2 ) and hypoxic (1% O2 )
Metformin exerted time- and dose-dependent effects on cell growth in HaCaT, human cervical adenocarcinoma cells (HeLa), and HSC-2 (Figure 1). It significantly inhibited the growth of HaCaT, HeLa, and HSC-2 after 96 h (p < 0.01, Figure 1a); under hypoxic conditions, metformin did not significantly affect HaCaT growth and the inhibitory effects of 1 mM metformin on the growth of HeLa and HSC-2 were abrogated (Figure 1b)
Summary
Most tumors are rich in hypoxic and nutrient-insufficient regions generally because of the high rate of proliferation of their cells and poor vascularization. Oxygen concentrations range between 3 and 9.8% in normal tissues in a tissue type-dependent manner [1,2]. Oxygen concentrations are highly heterogeneous in human tumors because of different vascular distribution, tissue types, variable intratumor blood flow, or environmental stress [1,3,4,5]. Metastatic cells scattered in the bloodstream may be exposed to high concentrations of oxygen. Low oxygen concentrations may drive genetic instability, mutations, and metabolic reprogramming in tumor cells, which allows these cells to adapt to harsh environments and induces aggressive tumor phenotypes [2,6,7,8,9]
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