Research Information System
MOLECULAR ONCOLOGY, vol.18, no.S1, pp.431, 2024 (SCI-Expanded)
Introduction
Alterations in the hypoxic tumour microenvironment and the development of hypoxia-associated chemoresistance arise when cells modify their energy metabolism through the Warburg effect. New therapeutic strategies are needed in this area as this mechanism can inactivate chemotherapeutic agents commonly used in colorectal cancer. This study aims to investigate the metabolic adaptation of metformin, an oral anti-diabetic drug, in a hypoxic environment and the reversibility of hypoxia- induced drug resistance.
Material and Methods
In this study, we investigated the effects of oxaliplatin combined with metformin, which is commonly used in the clinic, under normoxic and hypoxic conditions in HCT-116 and HT-29 colorectal cancer cell lines with different mutations using viability assay, wound healing assays and immunofluorescence staining to measure the expression levels of HIF-1 alpha, GLUT-1 and LDH-A. The chemical hypoxia method using sodium sulfite, which has been optimised in our previous studies, was used for the generation of hypoxic conditions.
Results and Discussions
No difference was observed between the results of oxaliplatin monotherapy and combined treatment with metformin under normoxic conditions. Under hypoxic conditions, oxaliplatin alone was ineffective compared to the control group. However, when combined with metformin, oxaliplatin was more effective. Furthermore, immunofluorescence results showed that the expression levels of E-cadherin, LDH-A, HIF-1alpha and GLUT-1, which were observed to be upregulated under hypoxic conditions, were downregulated under hypoxic conditions after combination treatment. These results were consistent with the wound healing assay, and hypoxic combined treatment decreased wound patency.Conclusion
We found that inhibition of HIF-1alpha, which is required for improved metabolic adaptation in hypoxia, had positive feedback on cell behaviour and drug effectiveness. Metformin, which inhibits HIF-1alpha, is hypothesised to increase metabolic activity in the tumour microenvironment. In this regard, metformin may be a novel therapeutic target to reverse hypoxia-associated drug resistance and metabolic adaptation in the hypoxic tumor microenvironment, especially to platinum.
O.B. was supported by TUBITAK 2211C Domestic Priority Doctoral Scholarship Program, and Council of Higher Education 100/2000 Scholarship in Priority Field Program. The study is supported by Presidency of Health Institutes of Turkey with project number 28664.