All-Trans Retinoic Acid Enhances Cytotoxicity ofCIK Cells Agains t Hepatocellular Carcinoma

Objective: To determine the increased sensitivity of pretreatedhepatocellular carcinoma cells with all-trans retinoic acid(ATRA) to enhance the cytotoxicity of cytokine-induced killercells (CIKs), we evaluated their effects, alone and in combination,on HepG۲ cell line.Materials and Methods: ATRA is currently used as a potentialchemo-preventive agent because of its anti-proliferative, proapoptoticand antioxidant properties. This s tudy inves tigatedthe effects of ATRA at different concentrations on the proliferationand the expression of MHC class I chain-related protein Aand B (MICA and MICB) on HepG۲ cell line. Moreover, theanti-tumor activity of CIK cells on the pretreated HCC cell linewith ATRA analyzed as well. Peripheral blood mononuclearcells (PBMC) from healthy donor were incubated in vitro andinduced into CIK cells in the presence of various cytokines. Thephenotype, characterization and cytotoxicity of CIK cells wereidentified by flow cytometry analysis. The effect of ATRA onthe proliferation and expression of MICA/B were examined byMTS assay and quantitative RT-PCR, respectively.Results: ATRA significantly inhibited the cell growth and increasedthe expression of MICA/B on HepG۲ cells in a dosedependentmanner. In addition, CIK cells could eradicatedcancerous cells through direct interaction between NKG۲D receptorand MICA/B ligand, which are expressed on the surfaceof CIK cells and on the surface of HCC cell lines, respectively.The combined application of two approaches can synergis ticallyboos t cytotoxicity of them through upregulated expression ofMICA and MICB on the HepG۲ after ATRA treatment.Conclusion: These results sugges t that combination of ATRAand CIK could be a potentially novel treatment protocol forhepatocellular carcinoma.

کلیدواژه ها:

All-Trans Retinoic Acid ، Cytokine-Induced KillerCells ، Hepatocellular Carcinoma ، Immunotherapy