Metformin and caffeic acid regulate metabolic reprogramming in human cervical carcinoma SiHa/HTB-35 cells and augment anticancer activity of Cisplatin via cell cycle regulation

Food Chem Toxicol. 2017 Aug;106(Pt A):260-272. doi: 10.1016/j.fct.2017.05.065. Epub 2017 May 30.


Metformin shows benefits in anticancer prevention in humans. In this study, normal human fibroblasts (FB) and metastatic cervical cancer cells (SiHa) were exposed to 10 mM Metformin (Met), 100 μM Caffeic Acid (trans-3,4-dihydroxycinnamic acid, CA) or combination of the compounds. Both drugs were selectively toxic towards cancer cells, but neither Met nor CA treatment suppressed growth of normal cells. Met and CA regulated metabolic reprogramming in SiHa tumor cells through different mechanisms: Met suppressed regulatory enzymes Glurtaminase (GLS) and Malic Enzyme 1 (ME1) and enhanced pyruvate oxidation via tricarboxylic acids (TCA) cycle, while CA acted as glycolytic inhibitor. Met/CA treatment impaired expression of Sterol Regulatory Element-Binding Protein 1 (SREBP1c) which resulted in alleviation of de novo synthesis of unsaturated fatty acid. The toxic action of CisPt was supported by Met and CA not only in tumor cells, but also during co-culture of SiHa GFP+ cells with fibroblasts. Furthermore, Met and CA augmented Cisplatin (CisPt) action against quiescent tumor cells involving reprogramming of cell cycle. Our findings provide new insights into specific targeting of mitochondrial metabolism in neoplastic cells and into designing new cisplatin-based selective strategies for treating cervical cancer in humans with regard to the role of tumor microenvironment.

Keywords: Apoptosis; Caffeic Acid; Cancer; Cisplatin; Metabolic reprogramming; Metformin.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Caffeic Acids / pharmacology*
  • Cell Cycle / drug effects*
  • Cell Line, Tumor
  • Cisplatin / pharmacology*
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Malate Dehydrogenase / genetics
  • Malate Dehydrogenase / metabolism
  • Metformin / pharmacology*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Uterine Cervical Neoplasms / drug therapy
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / physiopathology*


  • Antineoplastic Agents
  • Caffeic Acids
  • Sterol Regulatory Element Binding Protein 1
  • Metformin
  • Malate Dehydrogenase
  • malate dehydrogenase (decarboxylating)
  • Cisplatin
  • caffeic acid