Modulation of Regorafenib effects on HCC cell lines by epidermal growth factor

Journal Reference

Cancer Chemother Pharmacol. 2015;75(6):1237-45.

D’Alessandro R, Refolo MG, Lippolis C, Carella N, Messa C, Cavallini A, Carr BI.

Laboratory of Cellular and Molecular Biology, Department Clinical Pathology, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis”, Via Turi 27, 70013, Castellana Grotte, BA, Italy.



Blood platelet numbers are correlated to growth and aggressiveness of several tumor types, including hepatocellular carcinoma (HCC). We previously found that platelet lysates (hPLs) also stimulated growth and migration, and antagonized the growth-inhibitory and apoptotic effects of both Sorafenib and Regorafenib, two multikinase inhibitors, on three HCC cell lines. In this study, in vitro function of human epidermal growth factor(EGF) with and without Sorafenib or Regorafenib was investigated.


An ELISA kit was used to evaluate the EGF concentrations in hPLs. In vitro function of EGF was assessed with proliferation MTT test. Apoptosis assay, scratch assays, and Transwell assays were performed for apoptosis, invasion, and migration, respectively. MAPK Activation Kit was used to explore MAPK phosphorylation.


EGF antagonized the growth inhibition of  on three HCC cell lines. Regorafenib-mediated growth inhibition was blocked by 70 % when the cells were pre-treated with EGF. EGF also blocked Regorafenib-induced apoptosis, as well as Regorafenib-induced decreases in cell migration and invasion. The EGF effects were in turn antagonized by concomitant addition to the cultures of EGF receptor antagonist Erlotinib, showing that the EGF receptor was involved in the mechanisms of EGF-mediated blocking of Regorafenib effects. Erlotinib also partially blocked the effects of hPLs in antagonizing Regorafenib-mediated growth inhibition, showing that EGF was an important component of hPL actions.


All these results show that EGF antagonized Regorafenib-mediated growth and migration inhibition and apoptosis induction in HCCcells and reinforce the idea that microenvironment can influence cancer drug actions.

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About the author

Brian I. Carr MD, FRCP, PhD

Professor and Chief, Liver Cancer Program
Visiting Professor
Program for Targeted Experimental Therapeutics
Izmir Biomedicine and Genome Center
Dokuz Eylul University
35340 Balcova / Izmir / Turkey