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 journalArticle

Abstract

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
Volume19
Issue number5
DOIs
Publication statusPublished - May 19 2018

Fingerprint

Chlorogenic Acid
Hepatocellular Carcinoma
cancer
Cells
acids
Acids
Phosphatidylinositol 3-Kinase
progressions
drugs
Therapeutics
cells
Caspase 7
Chemotherapy
locomotion
regorafenib
Annexin A5
Cell proliferation
Cell growth
Polyphenols
staining

Keywords

  • 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

Cite this

Chlorogenic Acid Improves the Regorafenib Effects in Human Hepatocellular Carcinoma Cells. / Refolo, Maria Grazia; Lippolis, Catia; Carella, Nicola; Cavallini, Aldo; Messa, Caterina; D'Alessandro, Rosalba.

In: International Journal of Molecular Sciences, Vol. 19, No. 5, 19.05.2018, p. 1518.

Research output: Contribution to journalArticle

@article{74e7224e4ab5420e8cb3a73586d9269d,
title = "Chlorogenic Acid Improves the Regorafenib Effects in Human Hepatocellular Carcinoma Cells",
abstract = "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.",
keywords = "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",
author = "Refolo, {Maria Grazia} and Catia Lippolis and Nicola Carella and Aldo Cavallini and Caterina Messa and Rosalba D'Alessandro",
year = "2018",
month = "5",
day = "19",
doi = "10.3390/ijms19051518",
language = "English",
volume = "19",
pages = "1518",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "MDPI AG",
number = "5",

}

TY - JOUR

T1 - Chlorogenic Acid Improves the Regorafenib Effects in Human Hepatocellular Carcinoma Cells

AU - Refolo, Maria Grazia

AU - Lippolis, Catia

AU - Carella, Nicola

AU - Cavallini, Aldo

AU - Messa, Caterina

AU - D'Alessandro, Rosalba

PY - 2018/5/19

Y1 - 2018/5/19

N2 - 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.

AB - 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.

KW - Antineoplastic Agents/pharmacology

KW - Apoptosis/drug effects

KW - Cell Cycle/drug effects

KW - Cell Movement/drug effects

KW - Chlorogenic Acid/pharmacology

KW - Drug Synergism

KW - Hep G2 Cells

KW - Humans

KW - MAP Kinase Signaling System

KW - Mechanistic Target of Rapamycin Complex 1/metabolism

KW - Phenylurea Compounds/pharmacology

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Pyridines/pharmacology

U2 - 10.3390/ijms19051518

DO - 10.3390/ijms19051518

M3 - Article

C2 - 29783729

VL - 19

SP - 1518

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 5

ER -