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COMPARATIVE STUDY OF SODIUM OXAMATE AND METFORMIN CYTOTOXICITY AGAINST LEWIS LUNG CARCINOMA CELLS UNDER
D Kolesnik1, Y Stepanov1, I Prokhorova1
1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology of the NAS of Ukraine, Kyiv. Ukraine.
Background:
The effect of the inhibitors of glycolysis and oxidative phosphorylation on the altered metabolism of neoplasms is considered a promising method of antitumor therapy. However, most studies on the antimetastatic activity of such inhibitors focus on analyzing their effect on the migratory and invasive characteristics of cells. Meanwhile, the survival of circulating metastatic cells and their resistance to anoikis are critically important factors in metastasis.
Aim:
To carry out a comparative study of sodium oxamate (SOX) and metformin (MTF) effects on the survival, proliferative activity, and metabolic plasticity of the low-metastatic variant of Lewis lung carcinoma (LLC/R9) cells under their anchorage-independent growth.
Materials And Methods:
Cell death, apoptosis, cell cycle distribution, reactive oxygen species (ROS) production, glucose and lactate levels, and vimentin expression in LLC/R9 cells under their anchorage- independent growth were assessed following SOX and MTF treatments.
Results:
The cytotoxicity of inhibitors was manifested in a significant decrease in the number of viable LLC/R9 cells and an increase in the number of dead and apoptotic cells, the effects being more pronounced for MTF. In the case of SOX treatment, a correlation was observed between an increase in the percentage of apoptotic cells and ROS level and a decrease in the glucose consumption rate (GCR). MTF increased GCR and the number of apoptotic cells, without changes in ROS levels. Incubation with MTF resulted in a significant twofold increase in the percentage of cells in the S phase due to a decrease in the fraction of cells in the G1/G0 and G2/M phases of the cell cycle.
Conclusions:
Unlike SOX, the cytotoxic effect of MTF on de-adhesive cells was directly related to disrupting energy homeostasis and cell cycle regulation rather than by oxidative stress. Their combined application could potentially reinforce metabolic stress in circulating tumor cells, simultaneously weakening glycolytic and oxidative compensatory pathways, thereby limiting metastatic competence.
Insights
Metformin (MTF) and sodium oxamate (SOX) inhibit cancer cell growth. MTF disrupts energy and cell cycle regulation, while SOX increases oxidative stress, suggesting combined use may target circulating tumor cells.
Area of Science:
- Oncology
- Cancer Metabolism
- Metastasis Research
Background:
- Metabolic alterations in neoplasms are a target for antitumor therapy.
- Focus on antimetastatic activity often overlooks circulating tumor cell survival and anoikis resistance.
- Understanding metabolic plasticity is crucial for effective metastasis inhibition.
Purpose of the Study:
- Compare sodium oxamate (SOX) and metformin (MTF) effects on Lewis lung carcinoma (LLC/R9) cell survival and proliferation.
- Investigate the impact of SOX and MTF on metabolic plasticity during anchorage-independent growth.
- Assess the role of these inhibitors in overcoming anoikis resistance.
Main Methods:
- Assessed cell death, apoptosis, and cell cycle distribution in LLC/R9 cells.
- Measured reactive oxygen species (ROS) production, glucose consumption rate (GCR), and lactate levels.
- Evaluated vimentin expression under anchorage-independent conditions after SOX and MTF treatment.
Main Results:
- Both SOX and MTF reduced viable LLC/R9 cells, with MTF showing a more pronounced cytotoxic effect.
- SOX treatment correlated with increased apoptosis and ROS, and decreased GCR.
- MTF increased GCR and apoptosis without altering ROS, significantly shifting the cell cycle to S phase.
Conclusions:
- MTF's cytotoxicity on de-adhesive cells stems from energy homeostasis and cell cycle disruption, not oxidative stress.
- SOX primarily induces cytotoxicity via oxidative stress.
- Combined application of SOX and MTF could enhance metabolic stress in circulating tumor cells, inhibiting metastatic potential.
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