Combination therapy of sorafenib with mesenchymal stem cells as a novel cancer treatment regimen in xenograft models of hepatocellular carcinoma

Abstract

Aim Hepatocellular carcinoma (HCC) is the most common liver malignancy and the second leading cause of cancer‐related deaths in the world. Sorafenib is the first‐line treatment of HCC. Although sorafenib has positive effects on the survival of patients, novel therapeutic strategies are needed to extend survival and improve the efficacy of sorafenib. This study combines sorafenib with mesenchymal stem cells (MSCs) as a new approach to enhance the efficacy of sorafenib. Material and methods A subcutaneous xenograft model of HCC, established by human HepG2 cell lines, was implanted into the flank of nude mice and was used to evaluate tumor growth after treatment with sorafenib alone or in combination with MSCs. The aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine levels were measured for safety assessment. Histopathological studies were performed using hematoxylin and eosin staining, and immunohistochemistry tests were performed to evaluate proliferation (Ki67) and angiogenesis (CD34). The TUNEL assay was used to detect apoptosis and measure the expression of major inflammatory cytokines (IL‐1a, IL‐10, and TNF‐α) with real‐time polymerase chain reaction. Result Sorafenib, in combination with MSCs, strongly inhibited tumor growth in the xenograft model. Furthermore, the combination therapy significantly inhibited HCC cell proliferation, decreased tumor angiogenesis, and induced apoptosis and maintained antitumor‐associated anti‐inflammatory effects of MSCs. Conclusion This combination therapy strategy could be used as a new therapeutic approach to the treatment of HCC that significantly improves upon the results achieved using sorafenib as monotherapy.

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

“…As illustrated in Fig. 7, Sorafenib induced no signi cant effect on the expression levels of perforin, granzyme, IFN-γ and IL-6 (p value > 0.05), however, it signi cantly down regulated both IL-1 and TNF-α and induced the expression of IL-10 (p value < 0.05), as have been reported in our previous study (31). Most importantly, the gene expression levels of all the intended gene were the lowest in the mice treated with the combination of NKC & Sor, indicating no synergic effect of NK cells and Sorafenib (at speci c dose and time) against HCC tumors.…”

“…(27). 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) (28).…”

“…To implant heterotopic HepG2 tumors, as described in our previous studies (27,31). Brie y, 1 × 10 7 human HepG2 cells suspended in 200 μl of a 1:1 ratio of serum-free medium and Matrigel (Corning, product number: 354230, USA) were injected subcutaneously into the two anks of each animal.…”

The role of mesenchymal stem cells in the occurrence, development, and therapy of hepatocellular carcinoma

“…Conclusionally, the anti-tumor and anti-metastatic features of MSCs are retained by combined with sorafenib. 29,30 The inhibitory effect of MSCs-CM on the growth of liver cancer cells has been reported in several pieces of literature. Seyhoun et al further found that sorafenib combined with MSCs-CM also has a negative result on the growth of liver cancer cells.…”

MicroRNA-196a/-196b regulate the progression of hepatocellular carcinoma through modulating the JAK/STAT pathway via targeting SOCS2

“…The collected tumor tissues were used for further molecular studies. Cell apoptosis and proliferation in tumor tissues were measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining with in situ cell death detection kit (Roche, Mannheim, Germany) or Ki67 immunohistochemistry with anti-Ki67 antibody (ab16667, 1:1000 dilution, Abcam) following the manufacturer's instructions as previous study 20 .…”