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Synergistic antiproliferative effects of curcumin and celecoxib in hepatocellular carcinoma HepG2 cells

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Abstract

Hepatocellular carcinoma (HCC) is still a leading cancer killer in the community. Molecular targeted therapy with celecoxib (CXB) has shown promising antitumor effects; however, its use may be limited due to serious side effects. Curcumin (CUR) has also shown beneficial effects against HCC. Then, it was aimed to investigate the effects of adding CUR to CXB on HCC HepG2 cells. HepG2 cells were treated with CXB and/or CUR at increasing concentrations to investigate synergistic drug interactions, as calculated combination index (CI). Combination treatment effects on cell viability and caspase-3 activation were assessed. The levels of Akt, nuclear factor-kappa B (NF-κB), prostaglandin E2 (PGE2), malondialdehyde (MDA), cyclin D1 (CD1), and vascular endothelial growth factor (VEGF) were also evaluated. CXB (3.13–100 μM) and/or CUR (1.25–40 μM) reduced HepG2 cell viability dose-dependently. Nevertheless, lower combined concentrations showed higher synergism (CI < 1) and higher CXB dose reduction index (DRI > 1). Also, the addition of CUR to CXB resulted in increased cytotoxicity and caspase-3 activation, as compared to CXB alone. In addition, the selected combination significantly reduced the levels of Akt, NF-κB, PGE2, MDA, CD1, and VEGF, as compared to either agent alone. In conclusion, CUR augmented the CXB-mediated antitumor effects in HepG2 cells through, at least in part, antiproliferative, antioxidant, and pro-apoptotic mechanisms. This may allow the further use of CXB at lower concentrations, combined with CUR, as a promising safer targeted strategy for HCC management.

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Abbreviations

CD1:

Cyclin D1

CI:

Combination index

CUR:

Curcumin

CXB:

Celecoxib

DRI:

Dose reduction index

HCC:

Hepatocellular carcinoma

HepG2:

Human liver-derived hepatoma G2

DMEM:

Dulbecco’s modified eagle medium

FBS:

Fetal bovine serum

IC50 :

Median inhibitory concentration

MDA:

Malondialdehyde

MTT:

3-[4, 5-Dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide

NF-κB:

Nuclear factor kappa B

p-Akt:

Phospho-Akt

PGE2 :

Prostaglandin E2

SEM:

Standard error of the mean

VEGF:

Vascular endothelial growth factor

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Acknowledgments

The authors would like to thank the researchers at the Medical Technology Center of the Medical Research Institute (Alexandria, Egypt), as well as, Prof. Abdel-Hamid Zaki at the National Research Center (Cairo, Egypt) for technical support.

Author contribution statement

AG, MH, MK, and FA conceived and designed research. FA and MH conducted experiments. FA, MH, MK, and AG contributed materials, technical and analytical tools. FA, MH, and AG analyzed data. AG and FA wrote the manuscript. All authors read and approved the manuscript.

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The current research did not receive any grants from funding agencies in the public or commercial sectors.

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  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, Damanhour, 22514, Egypt

    Fatma M. Abdallah, Maged W. Helmy, Mohamed A. Katary & Asser I. Ghoneim

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  1. Fatma M. Abdallah
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  2. Maged W. Helmy
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Correspondence to Asser I. Ghoneim.

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The current research has followed accepted principles of ethical and professional conduct according to approval reference number (1116PO1) by the Research Ethics Committee of the Faculty of Pharmacy, Damanhour University, regarding originality, risk control, and community service.

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Abdallah, F.M., Helmy, M.W., Katary, M.A. et al. Synergistic antiproliferative effects of curcumin and celecoxib in hepatocellular carcinoma HepG2 cells. Naunyn-Schmiedeberg's Arch Pharmacol 391, 1399–1410 (2018). https://doi.org/10.1007/s00210-018-1557-6

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