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Open Access Research article

Antagonism of Sorafenib and Regorafenib actions by platelet factors in hepatocellular carcinoma cell lines

Rosalba D’Alessandro1, Maria G Refolo1, Catia Lippolis1, Grazia Giannuzzi2, Nicola Carella1, Caterina Messa1, Aldo Cavallini1 and Brian I Carr1*

Author Affiliations

1 Laboratory of Biochemistry, National Institute for Digestive Diseases, IRCCS “Saverio de Bellis”, Via Turi 27, 70013, Castellana Grotte, BA, Italy

2 Transfusion Medicine Center, “S. Maria degli Angeli” Hospital, via Cappuccini 7, 70017 Putignano, BA, Italy

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BMC Cancer 2014, 14:351  doi:10.1186/1471-2407-14-351

Published: 21 May 2014

Abstract

Background

Platelets are frequently altered in hepatocellular carcinoma (HCC) patients. Platelet lysates (hPL) can enhance HCC cell growth and decrease apoptosis. The aims were to evaluate whether hPL can modulate the actions of Sorafenib or Regorafenib, two clinical HCC multikinase antagonists.

Methods

Several human HCC cell lines were grown in the presence and absence of Sorafenib or Regorafenib, with or without hPL. Growth was measured by MTT assay, apoptosis was assessed by Annexin V and by western blot, and autophagy and MAPK growth signaling were also measured by western blot, and migration and invasion were measured by standard in vitro assays.

Results

Both Sorafenib and Regorafenib-mediated inhibition of cell growth, migration and invasion were all antagonized by hPL. Drug-mediated apoptosis and decrease in phospho-ERK levels were both blocked by hPL, which also increased anti-apoptotic phospho-STAT, Bax and Bcl-xL levels. Preliminary data, obtained with epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I), included in hPL, revealed that these factors were able to antagonized Sorafenib in a proliferation assay, in particular when used in combination.

Conclusions

Platelet factors can antagonize Sorafenib or Regorafenib-mediated growth inhibition and apoptosis in HCC cells. The modulation of platelet activity or numbers has the potential to enhance multikinase drug actions.

Keywords:
Regorefenib; Platelets; HCC; Apoptosis; Growth; Invasion