Abstract
Abstract Background. Platelet numbers are related to growth and aggressiveness of several tumor types, including hepatoma (hepatocellular carcinoma). We previously found that platelet lysates also stimulated growth and migration of hepatoma lines in vitro and antagonized the growth-inhibitory effects on hepatoma cells of both multikinase inhibitors sorafenib and regorafenib (BMC Cancer 2014; 14:351). Aims. To investigate the mechanisms for the platelet-mediated multikinase drug resistance, we examined the actions of several mitogens that are known to be contained by platelets (PDGF, VEGF, TGF beta, FGF, IGF-1, EGF). Results. We found that epidermal growth factor (EGF) alone antagonized the growth inhibitory actions of Sorafenib or Regorafenib on HepG2, PLC/PRF/5 and Hep3B human hepatoma cells, using an MTT assay. Detailed studies revealed that EGF also antagonized Regorafenib-mediated inhibition of cell migration and invasion. Furthermore, EGF also blocked regorafenib-induced apoptosis, measured by Annexin V using a MUSE cell analyzer. These effects of EGF were 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. In addition, Erlotinib also partially blocked the effects of platelet lysates in antagonizing regorafenib-mediated growth inhibition. Similar antagonism was found using IGF-1, and those effects were blocked by GSK IGF-1 receptor antagonist. Other platelet factors had only weak actions in these assays. Conclusions. EGF antagonized regorafenib-mediated growth and migration inhibition and apoptosis induction in hepatoma cells. These EGF actions were mediated via the EGF receptor, as were the similar platelet lysate actions. Citation Format: Brian I. Carr, Rosalba D'Alessandro, Maria Grazia Refolo, Catia Lippolis, Caterina Messa, Aldo Cavallini. Antagonism of sorafenib and regorafenib actions by epidermal growth factor in hepatoma cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5501. doi:10.1158/1538-7445.AM2015-5501
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