Oncolytic adenovirus SG600-IL24 selectively kills hepatocellular carcinoma cell lines

Xue, Xindong; Xiao, Chaowen; Zhang, Hui; Lu, Aiguo; Gao, Wei; Zhou, Zhuqing; Guo, Xinlai; Zhong, Mingan; Yao, Yang; Wang, Congjun

doi:10.3748/wjg.v16.i37.4677

Cited by 10 publications

(11 citation statements)

References 35 publications

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“…Importantly, p63 and p73 isoforms were not sufficient to compromise Adp53sensor replication, demonstrating that this approach was not restricted by other p53 family members in HCC cells [111]. Thus, novel virotherapeutic strategies based on p53 integrity may overcome limitations of previous oncolytic approaches and some studies suggested that HCC cells are promising targets [112,113].…”

Section: Gene Therapeutic Approachesmentioning

confidence: 93%

Transcriptional regulators in hepatocarcinogenesis – Key integrators of malignant transformation

Malz

Pinna

Schirmacher

et al. 2012

Journal of Hepatology

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Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies with poor prognosis and increasing incidence in the Western world. Only for a minority of HCC patients, surgical treatment options offer potential cure and therapeutic success of pharmacological approaches is limited. Highly specific approaches (e.g., kinase inhibitors) did not significantly improve the situation so far, possibly due to functional compensation, genetic heterogeneity of HCC, and development of resistance under selective pressure. In contrast, transcriptional regulators (especially transcription factors and co-factors) may integrate and process input signals of different (oncogenic) pathways and therefore represent cellular bottlenecks that regulate tumor cell biology. In this review, we want to summarize the current knowledge about central transcriptional regulators in human hepatocarcinogenesis and their potential as therapeutic target structures. Genomic and transcriptomic data of primary human HCC revealed that many of these factors showed up in subgroups of HCCs with a more aggressive phenotype, suggesting that aberrant activity of transcriptional regulators collect input information to promote tumor initiation and progression. Therefore, expression and dysfunction of transcription factors and co-factors may gain relevance for diagnostics and therapy of HCC.

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Section: Gene Therapeutic Approachesmentioning

confidence: 93%

Transcriptional regulators in hepatocarcinogenesis – Key integrators of malignant transformation

Malz

Pinna

Schirmacher

et al. 2012

Journal of Hepatology

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“…Recently, a number of scientific reports have described oncolytic Ads armed with the mda-7 /IL-24 gene, for example, SG600-IL24, an oncolytic Ad harboring mda-7 /IL-24 selectively induces apoptosis in different hepatocarcinoma cell lines without affecting a normal liver cell line (Xue et al, 2010). In another approach, an E1B-55K d deleted oncolytic Ad car rying mda-7 /IL-24 was developed (ZD-55-IL-24) that exhibited better therapeutic efficacy compared with ONXY-015 against hepatic cancer (Xiao et al, 2010).…”

Section: Cancer Terminator Viruses: Efficacious Reagents For Cancementioning

confidence: 99%

Cancer Terminator Viruses and Approaches for Enhancing Therapeutic Outcomes

Das

Sarkar

Dash

et al. 2012

Advances in Cancer Research

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No single or combinatorial therapeutic approach has proven effective in decreasing morbidity or engendering a cure of metastatic cancer. In principle, conditionally replication-competent adenoviruses that induce tumor oncolysis through cancer-specific replication hold promise for cancer therapy. However, a single-agent approach may not be adequate to completely eradicate cancer in a patient because most cancers arise from abnormalities in multiple genetic and signal transduction pathways and targeting disseminated metastases is difficult to achieve. Based on these considerations, a novel class of cancer destroying adenoviruses have been produced, cancer terminator viruses (CTVs), in which cancer-specific replication is controlled by the progression-elevated gene-3 promoter and replicating viruses produce a second transgene encoding an apoptosis-inducing and immunomodulatory cytokine, either melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) or interferon-γ. This review focuses on these viruses and ways to improve their delivery systemically and enhance their therapeutic efficacy.

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“…Second, adenovirus type 5 specifically binds to hepatocytes via coagulation factor X and heparin sulfate proteoglycans [25]. Replication-competent oncolytic adenovirus SG600-IL-24 has the telomerase reverse transcriptase promoter (TERTp) and the hypoxia regulatory elements (HRE) controlling the expression of adenoviral mutated E1a gene and the E1b, respectively [26-28]. Mutation of the E1a gene and its expression driven by the telomerase promoter hinders its replication in normal cells but not in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore SG600-IL-24 has enhanced effectiveness and safety for cancer gene therapy. We have recently shown that SG600-IL-24 inhibits growth and increases apoptosis of several HCC cell lines in vitro [27,28]. The in vitro anti-tumor activity of oncolytic adenovirus SG600-IL-24 was significantly greater than that of replication defective adenovirus IL-24 [27].…”

Section: Introductionmentioning

confidence: 99%

Interferon-α enhances antitumor activities of oncolytic adenovirus-mediated IL-24 expression in hepatocellular carcinoma

et al. 2012

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BackgroundHepatocellular carcinoma (HCC) has a dismal 5-year-survival rate of 10%, so novel strategies are warranted. IL-24 mediates anti-tumor activity reducing STAT3 expression, which suggests that interferon (IFN) alpha may augment tumor cell lysis and reduce angiogenesis. We investigated the antitumor activity of treatment with IFN-α, with the oncolytic adenovirus SG600-IL-24, or the combination of both in HCC in vitro and in vivo.ResultsRT-PCR, ELISA assay and Western-blot confirmed that the exogenous IL-24 gene was highly expressed in HCC cells infected with SG600-IL-24. Treatment with combined IFN-α and SG600-IL-24 suppressed growth and promoted apoptosis of the HepG2, MHCC97L, and HCCLM3 cell lines compared with the normal cell line L02. The combined therapy increased STAT1 and SOCS1 and apoptosis, but decreased the expression of the metastatic and angiogenic proteins MMP-2, XIAP, OPN, and VEGF, which are regulated by STAT3 in HCC cells in vitro. To assess the effects in vivo, the HCC cell line HCCLM3 was transplanted subcutaneously into the right flanks of nude mice. Mice in the IFN-α group, the SG600-IL-24 group, or the combined therapy group had significantly suppressed growth of the HCC xenografted tumors compared to the PBS control group of mice. Among the mice treated with the combination of IFN-α and SG600-IL-24, three of those eight mice had long-term survival and no evidence of a tumor. These mice also had decreased expression of the metastatic and angiogenic proteins MMP-2, XIAP, OPN, and VEGF.ConclusionsThe present study demonstrated for the first time the potential antitumor activity of IFN-α combined with the oncolytic adenovirus SG600-IL-24 in HCC both in vitro and in vivo, and suggests its further development as a potential candidate for HCC cancer gene therapy.

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Oncolytic adenovirus SG600-IL24 selectively kills hepatocellular carcinoma cell lines

Abstract: SG600-IL24 can selectively suppress the proliferation and apoptosis of HCC cell lines in vitro but not normal liver cell line L02 in a p53-independent manner. Compared with Ad.IL-24, SG600-IL24 can significantly enhance the antitumor activity in HCC cell lines.

Cited by 10 publications

References 35 publications

Transcriptional regulators in hepatocarcinogenesis – Key integrators of malignant transformation

Transcriptional regulators in hepatocarcinogenesis – Key integrators of malignant transformation

Cancer Terminator Viruses and Approaches for Enhancing Therapeutic Outcomes

Interferon-α enhances antitumor activities of oncolytic adenovirus-mediated IL-24 expression in hepatocellular carcinoma

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