Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions

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.

Triple Therapy with Metformin, Ketogenic Diet, and Metronomic Cyclophosphamide Reduced Tumor Growth in MYCN-Amplified Neuroblastoma Xenografts

“…Despite the striking effects on respiration, this was not paralleled by similar reductions in cell proliferation, pointing to the metabolic flexibility of MYCN-amplified NB cells to sustain growth when challenged by metabolic impairments. This phenomenon is in agreement with other studies showing that the metabolic environment may determine sensitivity of cancer cells to MET [ 53 , 54 , 55 , 56 ]. In support of this notion, we observed either a partial disruption to tumor growth, or no response at all, in MYCN-amplified NB xenografts treated with MET alone ( Figure S2 ) or in combination with CP ( Figure 4 ).…”

Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing

“…It can be administered along with chemotherapy, radiotherapy, immunotherapy or targeted therapy. Taking immunotherapy as an example, a high level of lactate can lead to tumor immune tolerance, while metformin was reported to increase the level of lactate in the intra- and extracellular environment [ 31 , 185 ]. However, from the current evidence, acidification of the TME made tumors more susceptible to metformin due to the loss of NAD+ regeneration capacity [ 78 , 79 , 186 ].…”

Metformin and Cancer Hallmarks: Molecular Mechanisms in Thyroid, Prostate and Head and Neck Cancer Models

“…Similarly, in OSCC cells, metformin inhibited proliferation but decreased cisplatin toxicity [125], an effect that can be reverted under glucose deprivation conditions [126]. In fact, glucose starvation can enhance antiproliferative effects of metformin in resistant OSCC cells and be modulated by oxygen levels [127]. In contrast, in another study, HPV-positive HNSCC cells were sensitized to ionizing radiation after combined treatment of metformin and 2-deoxy-D-glucose [128].…”