Comparison of the Effects of Sorafenib and Stem Cell Secretome on HepG2 Cancer Cells with Respect to the Ras/Raf/MEK/ERK Pathway.

Background/Objective: Liver cancer is a global health challenge due to its resistance to most systemic therapies. Human mesenchymal and epithelial stem cells exhibit anti-proliferative and pro-apoptotic effects on some cancer cell lines, which can be used to support standard therapy. The aim of this study was to investigate the effects of conditioned media (CM) derived from mesenchymal adipose tissue-derived stem cells (hADSCs) and amniotic membrane-derived cells expressing both mesenchymal and epithelial markers (hACs) on HepG2 liver cancer cells in vitro and to identify possible similarities to the action of sorafenib, a standard drug in hepatocellular carcinoma (HCC) therapy. Methods: HepG2 cells were cultured with hADSC-derived CM (CM-hADSC) or hAC-derived CM (CM-hAC), either alone or with 7.5 μm sorafenib for 48 h. HepG2 cell viability and the expression of genes and/or proteins related to the apoptosis, cell-cycle, and Ras/Raf/MEK/ERK signaling pathway, were assessed. Results: The effect of sorafenib administration alone, consisting in reducing HepG2 cell viability, cell cycle inhibition, and reducing the expression of the alpha-fetoprotein (AFP) gene and most proteins related to the Ras/Raf/MEK/ERK pathway, was dominant over the effect of CM administered in combination with one of them. The effect of sorafenib on increasing the number of early apoptotic cells was not associated with increased Bax protein expression or with an increased proportion of cleaved forms of caspase-7 and caspase-9. The effect of CM-hAC was often different from that of CM-hADSC and consisted in enhancing the inhibitory effect of sorafenib at the cell cycle level and increasing the number of apoptotic cells and caspase mRNA expression, while activating the Ras/Raf/MEK/ERK signaling pathway and inducing AFP gene expression. Conclusions: Combined administration of sorafenib and some CM may produce the desired effects by enhancing the action of the drug. However, some of the effects of sorafenib and CM derived from different stem cell types were significantly different, which means that the role of stem cell secretome as a potential anticancer therapy requires further investigation, taking into account different types of cancer cell lines and a thorough analysis of the secretome composition.