Synergistic growth inhibition by acyclic retinoid and phosphatidylinositol 3-kinase inhibitor in human hepatoma cells
Menée sur une lignée cellulaire de carcinome hépatocellulaire humain, cette étude analyse les effets combinés d'un rétinoïde acyclique et d'un inhibiteur de la phosphatidylinositol-3-kinase sur la croissance des cellules tumorales
Background : A malfunction of RXRalpha due to phosphorylation is associated with liver carcinogenesis, and acyclic retinoid (ACR), which targets RXRalpha, can prevent the development of hepatocellular carcinoma (HCC). Activation of PI3K/Akt signaling plays a critical role in the proliferation and survival of HCC cells. The present study examined the possible combined effects of ACR and LY294002, a PI3K inhibitor, on the growth of human HCC cells. Methods : This study examined the effects of the combination of ACR plus LY294002 on the growth of HLF human HCC cells. Results : ACR and LY294002 preferentially inhibited the growth of HLF cells in comparison with Hc normal hepatocytes. The combination of 1 muM ACR and 5 muM LY294002, in which the concentrations used are less than the IC50 values of these agents, synergistically inhibited the growth of HLF, Hep3B, and Huh7 human HCC cells. These agents when administered in combination acted cooperatively to induce apoptosis in HLF cells. The phosphorylation of RXRalpha, Akt, and ERK proteins in HLF cells were markedly inhibited by treatment with ACR plus LY294002. Moreover, this combination also increased RXRE promoter activity and the cellular levels of RARbeta and p21CIP1, while decreasing the levels of cyclin D1. Conclusion : ACR and LY294002 cooperatively increase the expression of RARbeta, while inhibiting the phosphorylation of RXRalpha, and that these effects are associated with the induction of apoptosis and the inhibition of cell growth in human HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.