Chlorogenic Acid Improves the Regorafenib Effects in Human Hepatocellular Carcinoma Cells

Maria Grazia Refolo, Catia Lippolis, Nicola Carella, Aldo Cavallini, Caterina Messa, Rosalba D'Alessandro

Research output: Contribution to journalArticlepeer-review


Chlorogenic acid (CGA) is a polyphenol present in many human dietary foods. Several studies indicated a beneficial role of CGA in the prevention of cancer and an enhancement of chemotherapy when combined with CGA in the treatment of human hepatocarcinoma (HCC). Drug toxicity, resistance and subsequent disease progression represent a problem in HCC management, although treatment with the multikinase inhibitor Regorafenib improved overall survival. This study focused on the evaluation of the effects of combined treatment using both low Regorafenib concentrations and CGA as natural compound in HCC cells. The analysis of cell proliferation by Ki67 staining and cell cycle progression showed that CGA enhanced Regorafenib-mediated cell growth inhibition. Moreover, CGA potentiated the apoptotic effect of Regorafenib by the activation of the pro-apoptotic Annexin V, Bax and Caspase 3/7 and the inhibition of anti-apoptotic Bcl2 and Bcl-xL. Combined treatments were also effective in inhibiting cell motility. The mechanisms underlying the positive effects of combining CGA and Regorafenib were also addressed and an increased inhibition of MAPK (mitogen-activated protein kinase)and PI3K/Akt/mTORC (phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling was observed. Overall, these data demonstrated that co-treatment with Regorafenib and CGA enhanced Regorafenib action, reducing its cytotoxicity in HCC cells. In conclusion, this drug combination could be considered as a safe and more effective approach in HCC therapy.

Original languageEnglish
Pages (from-to)1518
Number of pages16
JournalInternational Journal of Molecular Sciences
Issue number5
Publication statusPublished - May 19 2018


  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Cell Cycle/drug effects
  • Cell Movement/drug effects
  • Chlorogenic Acid/pharmacology
  • Drug Synergism
  • Hep G2 Cells
  • Humans
  • MAP Kinase Signaling System
  • Mechanistic Target of Rapamycin Complex 1/metabolism
  • Phenylurea Compounds/pharmacology
  • Phosphatidylinositol 3-Kinases/metabolism
  • Proto-Oncogene Proteins c-akt/metabolism
  • Pyridines/pharmacology


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