title: Combination of metformin and valproic acid synergistically induces cell cycle arrest and apoptosis in clear cell renal cell carcinoma.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University Shanghai, China ; Department of Urology, Shaoxing People's Hospital, Zhejiang University Shaoxing, Zhejiang, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University Shanghai, China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University Shanghai, China.
authors.forename: Tianbao
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University Shanghai, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Geng
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University Shanghai, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Urology, Shanghai Tenth People's Hospital, Tongji University Shanghai, China.
authors.forename: Junhua
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D014635:Valproic Acid; D008687:Metformin
keywords: Combination; metformin; renal cell carcinoma; valproic acid