Combination of metformin and valproic acid synergistically induces cell cycle arrest and apoptosis in clear cell renal cell carcinoma.

OBJECTIVE

To investigate the antitumor activity of metformin combined with valproic acid (VPA) on renal cell carcinoma (RCC) cell lines.

METHODS

The effects of metformin combined with VPA on the viability of 786-O and caki-2 cell lines were evaluated by MTT assay. The inhibitory effect of combination of the two drugs was analyzed by the Chou and Talalay method. Flow cytometry was employed to analyze cell cycle and cell apoptosis.

RESULTS

MTT assay showed that both metformin and VPA decreased 786-O and Caki-2 cells viability in a dose-dependent and time-dependent manner. In 786-O cells, metformin combined with VPA had a synergistic inhibitory effect (CI<1) when the inhibition effect was ≥0.3. In Caki-2 cells, metformin combined with VPA had a synergistic inhibitory effect (CI<1) when the inhibition effect was ≥0.4. Metformin and VPA combination elicited significant apoptosis compared to drug used alone (P<0.05). Furthermore, metformin and VPA acted synergistically to arrest 786-O and Caki-2 cells in G0/G1 phase.

CONCLUSION

We highlighted for the first time that metformin combined with VPA could significantly increase anti-ccRCC effect through synergetic effect; its possible mechanisms were inducing apoptosis and adjusting cell cycle.