Synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 and oxaliplatin via p53-independent pathway in vitro and in vivo

Abstract

The present study was designed to investigate the synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 (Aspp2-ad) and oxaliplatin via p53-independent pathway in vitro and in vivo. After being treated with Aspp2-ad and/or oxaliplatin for 24-48 h, HepG2P53-/- and Hep3B cells showed a significant growth inhibition compared with vehicle control. Combination group showed a synergetic effect, the inhibitory rates were all above 80% at 48 h point in HepG2P53-/- and Hep3B cells. The apoptotic cell numbers of Aspp2-ad and/or oxaliplatin treatment groups were increased remarkably, especially for the combined therapy group in the liver cancer cells. The Hep3B xenograft experiment also showed similar inhibition of Aspp2-ad and/or oxaliplatin to the in vitro experiment. H&E results showed that combination group had the least mitotic indexes and the most necrosis. The immunohistochemistry results showed that PCNA, CD31 expression decreased greatly in treatment groups. These results suggested that Aspp2-ad might inhibit proliferation and vascular growth of hepatocarcinoma. Aspp2 induced apoptosis protein expression in Aspp2-ad and combination groups, the Aspp2, Bax and activation of caspase-3 expression increased greatly both in vitro and in vivo. But interestingly, the autophagy proteins showed different responses not only in HepG2P53-/- and Hep3B cells but also in vitro and in vivo. We found that Aspp2-ad downregulated the p-ERK, p-STAT3 expression, the synergistic effects were observed in combination group, while there was not response of mTOR to Aspp2-ad. In conclusion, Aspp2-ad, in P53-independent manner, regulated ERK and STAT3 signal moleculars to inhibit hepatocarcinoma in coordination with oxaliplatin by influencing the protein expression of proliferation, apoptosis, autophagy and vascular growth. Aspp2-ad has the potential to be developed in gene therapy for HCC, especially for P53 deletion or mutation in HCC.

GW4064 Enhances the Chemosensitivity of Colorectal Cancer to Oxaliplatin by Inducing Pyroptosis

“…The combination of oxaliplatin plus GW4064 inhibits STAT3 signaling by restoring SHP expression Small heterodimer partner (SHP), a well-known target gene of FXR, inhibits tumorigenesis by repressing STAT3 activity (35). Various lines of evidence have established that oxaliplatin could decrease the expression of STAT3 to inhibit the progression of cancer (36,37). As expected, GW4064 treatment alone increased the protein level of SHP.…”

Oncolytic Adenovirus—A Nova for Gene-Targeted Oncolytic Viral Therapy in HCC

“…Furthermore, an increasing amount of research has reported that oncolytic adenoviruses are capable of infecting and expressing exogenous functional genes with no target cells. The functional/effector genes can be classified in four categories by their functions: (1) Tumor-suppressor gene (51, 52); (2) Cytotoxic gene; (3) Immune-modulating gene (53); (4) Tumor-antigens (54). The following is the detailed introduction of genes carried by oncolytic adenoviral vectors for HCC treatment.…”

“…p53 is determined as a novel tumor-associated gene which mutations or deletions are related to most of the cancer formation. Since the frequency of p53 gene mutation/deletion is as high as 50.0% (average, 30.0%) in HCC (51), converting abnormal conformations of mutant p53 to normal p53 or enhancing the apoptosis of tumor cells by providing the exogenous p53 gene and the associated genes becomes a promising therapeutic strategy. The recombinant human wild-type p53-carrying adenovirus (Gendicine) is a pioneer gene therapy product approved for clinical use in China (66, 67).…”

“…Liu et al demonstrated that Aspp2 increased colorectal cancer sensitivity to chemotherapy, especially to oxaliplatin, via inhibiting autophagy in a p53-independent pathway (70). Later on, they had generated a recombinant human adenovirus vector carrying the Aspp2 gene for use in HCC treatment in combination with oxaliplatin and found that Assp2-Ad inhibits hepatocarcinoma, independently of p53, in coordination with oxaliplatin (51).…”

Napabucasin Reduces Cancer Stem Cell Characteristics in Hepatocellular Carcinoma

“…The potential cytotoxic effect of napabucasin on HCC cells was evaluated in terms of the proliferation ability of multiple human and murine HCC cell lines, and compared to that of oxaliplatin and the plant-derived STAT3 inhibitor cryptotanshinone (Liu et al, 2017;Qin et al, 2017;Ji et al, 2019;Zhu et al, 2019). As shown in Figure 1, all drugs significantly decreased the viability of HCC cells in a concentration-dependent manner.…”