The Effects of Sorafenib and Natural Killer Cell Co-injection in Combinational Treatment of Hepatocellular Carcinoma; In Vivo

Abstract Background: Natural killer cells (NKC) and Sorafenib (Sor) are two important agents for treatment of Hepatocellular Carcinoma (HCC). Over the last decade, the interaction of Sor and NKC against HCC tumors has been very challenging. This study aimed to assess the efficacy of combination therapy of NKC plus Sor for HCC in vivo. Methods: Subcutaneous xenograft models of HCC were established in nude mice. For safety assessment of the treatment, the kidney and liver functions were analyzed. Paraffin embedded tumor sections were histopathologically studied and IHC tests were done to evaluate the angiogenesis (CD34) and proliferation (Ki67) indexes. The TUNEL assay was performed to identify tumor apoptosis. Serum levels of TNF-α and IFN-γ were measured by ELISA assay and expression levels of major inflammatory cytokines and cytoplasmic granules in xenograft HCC tumors were quantified by using real-time PCR. Results: Combination therapy with NKC and Sor significantly inhibited necrosis and apoptosis in tumor cells and increased angiogenesis and proliferation of HCC cells compared to monotherapy of NKC or Sor alone. The serum levels of TNF-α, IFN-γ as well as the expression levels of TNF-α, IFN-γ, ILs-1, 6 and 10, granzyme B and perforin in the xenograft HCC tumor tissues of mouse treated with both NKC and Sor were significantly decreased than those detected in xenograft HCC groups treated with NKC or Sor alone. Conclusion: Combination therapy of the specific dosage of NKC and Sor cannot inhibit the HCC xenograft growth rate through a synergistic effect. All experimental procedures were performed according to the National Institutes of Health (NIH) guide for the care and use of Laboratory animals and were approved by the Institutional Ethical Committee of Tehran University (IECTU) of Medical Sciences (IR.TUMS.VCR.REC.1397.181)