Enhancement of anti-proliferative activities of Metformin, when combined with Celecoxib, without increasing DNA...

Area of Science:

• Pharmacology
• Toxicology
• Cell Biology

Background:

• Diabetes mellitus complications include hyperglycemia, oxidative stress, and insulin resistance, which can promote malignant transformation.
• These conditions can also impair DNA repair mechanisms, increasing susceptibility to cellular damage.
• Investigating drug interactions is crucial for understanding potential therapeutic and toxicological effects.

Purpose of the Study:

• To explore the synergistic toxic effects of Metformin (anti-diabetic) and Celecoxib (analgesic) at the cellular level.
• To evaluate the impact of this drug combination on cell proliferation and DNA integrity.
• To assess the genotoxic and mutagenic potential of the combined drug treatment.

Main Methods:

• MTT assay was used to determine the anti-proliferative effects of Metformin and Celecoxib on Vero cell lines.
• Single-cell gel electrophoresis (comet assay) was employed to assess DNA damage in peripheral blood mononuclear cells.
• Bacterial reverse mutation assays (Ames test) were performed to evaluate mutagenicity.

Main Results:

• The combination of Metformin and Celecoxib demonstrated augmented anti-proliferative effects.
• Celecoxib induced significant DNA damage (Class III comets) at concentrations above 75 μg/ml, while Metformin showed non-significant DNA damage up to 400 μg/ml.
• The combination of drugs resulted in less DNA damage than Celecoxib alone and exhibited slight mutagenicity only at very high concentrations.

Conclusions:

• Metformin and Celecoxib synergistically inhibit cell proliferation in a concentration-dependent manner.
• The observed increase in cytotoxicity did not correlate with increased DNA damage or mutagenicity.
• This drug combination holds promise for inhibiting malignant cell growth without inducing genotoxic or mutagenic effects at the cellular level.