Abstract 259: Modulation of doxorubicin actions on HCC cells by insulin-like growth factor-I

Abstract

Listen

Translate article

Abstract Tumor microenvironment is increasingly understood to influence tumor biology in many tumor types, including HCC. We recently showed that platelets could modulate Doxorubicin (Dox)-mediated HCC growth inhibition (Refolo MG et al. Modulation of doxorubicin mediated growth inhibition of hepatocellular carcinoma cells by platelet lysates. Anticancer Agents Med Chem. 2014;14:1154-60). Platelets contain cytokines and growth factors, including IGF-1, PDGF, FGF, EGF and serotonin. We found that Insulin-like growth factor-1 (IGF-1) shifted the Dox growth-inhibitory dose-response in the range of 0.1-1.0 μM on Hep3B, HepG2, PLC/PRF/5 human HCC lines, all of which became less sensitive to both Dox-mediated inhibition of growth and apoptosis. Similar antagonism by IGF-1 was found for Dox-mediated inhibition of cell migration (scratch assay) and invasion (Boyden chamber). This antagonism of Dox effects on cell growth, migration and apoptosis by IGF1, was blocked by GSK1838705A, an IGF-1R inhibitor. Furthermore, when platelet extracts were used to antagonize Dox inhibition of growth and migration, the platelet effects were also blocked by addition of GSK1838705A to the cultures, showing that the platelet effects were largely mediated by IGF-1. Dox caused a decrease in the levels of anti-apoptosis markers Bcl-2, Bcl-xL and survivin as seen on WB, whereas levels of all three anti-apoptosis markers were increased by IGF-1 action. These actions of IGF-1 were also blocked by GSK 1838705A. Furthermore, Dox caused a decrease in the levels of P-ERK, P-p38 and P-STAT3 (ser727). These signaling molecule decreases were also reversed by the presence of IGF-1. Conclusions. Dox actions on HCC cells can be antagonized by platelets and specifically by platelet-associated IGF-1. IGF-1 antagonists appear to be attractive enhancers of sensitivity to Dox actions. Citation Format: Brian I. Carr, Maria Grazia Refolo, Rosalba D’Alessandro, Nicola Carella, Caterina Messa, Aldo Cavallini. Modulation of doxorubicin actions on HCC cells by insulin-like growth factor-I. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 259.