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Potent and specific antitumor effect for colorectal cancer by CEA and Rb double regulated oncolytic adenovirus harboring ST13 gene.

ABSTRACT: Cancer Targeting Gene-Viro-Therapy (CTGVT) is constructed by inserting an antitumor gene into an oncolytic virus (OV). It is actually an OV-gene therapy, which has much better antitumor effect than either gene therapy alone or virotherapy alone in our previously published papers. This study is a modification of CTGVT by inserting a colorectal cancer (CRC) specific suppressor gene, ST13, into a CRC specific oncolytic virus, the Ad·CEA·E1A(?24), to construct the Ad·(ST13)·CEA·E1A(?24) for increasing the targeting tropism to colorectal cancer and it was briefly named as CTGVT-CRC. Although many studies on CEA promoter and ST13 gene were reported but no construct has been performed to combine both of them as a new strategy for colorectal cancer (CRC) specific therapy. In addition to the CRC specificity, the antitumor effect of Ad·(ST13)·CEA·E1A(?24) was also excellent and got nearly complete inhibition (not eradication) of CRC xenograft since ST13 was an effective antitumor gene with less toxicity, and a Chinese patent (No. 201110319434.4) was available for this study. Ad·(ST13)·CEA·E1A(?24) caused cell apoptosis through P38 MAPK (i.e. P38) which upregulated CHOP and ATF2 expression. The mitochondrial medicated apoptosis pathway was activated by the increase of caspase 9 and caspase 3 expression.

SUBMITTER: Zhou X

PROVIDER: S-EPMC3471845 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Potent and specific antitumor effect for colorectal cancer by CEA and Rb double regulated oncolytic adenovirus harboring ST13 gene.

Zhou Xiumei X Xie Guoliang G Wang Shibing S Wang Yigang Y Zhang Kangjian K Zheng Shu S Chu Liang L Xiao Lianli L Yu Yuemei Y Zhang Yue Y Liu Xinyuan X

PloS one 20121015 10

Cancer Targeting Gene-Viro-Therapy (CTGVT) is constructed by inserting an antitumor gene into an oncolytic virus (OV). It is actually an OV-gene therapy, which has much better antitumor effect than either gene therapy alone or virotherapy alone in our previously published papers. This study is a modification of CTGVT by inserting a colorectal cancer (CRC) specific suppressor gene, ST13, into a CRC specific oncolytic virus, the Ad·CEA·E1A(Δ24), to construct the Ad·(ST13)·CEA·E1A(Δ24) for increasi ...[more]

PMID: 23077639

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Project description:BackgroundSystemic administration of oncolytic adenovirus for cancer therapy is still a challenge. Mesenchymal stem cells as cell carriers have gained increasing attention in drug delivery due to their excellent tumor tropism, immunosuppressive modulatory effects, and paracrine effects. However, the potential of human dental pulp stem cells (hDPSCs) loaded with oncolytic adenovirus for cancer biotherapy has not been investigated yet.MethodsThe stemness of hDPSCs was characterized by FACS analysis and Alizarin red staining, Oil Red O staining, and immunofluorescence assays. The biological fitness of hDPSCs loaded with oncolytic adenovirus YSCH-01 was confirmed by virus infection with different dosages and cell viability CCK-8 assays. Additionally, the expression of CAR receptor in hDPSCs was detected by qPCR assay. Tumor tropism of hDPSC loaded with YSCH-01 in vitro and in vivo was investigated by Transwell assays and living tumor-bearing mice imaging technology and immunohistochemistry, Panoramic scanning of frozen section slices assay analysis. Furthermore, the antitumor efficacy was observed through the different routes of YSCH-01/hPDSCs administration in SW780 and SCC152 xenograft models. The direct tumor cell-killing effect of YSCH-01/hDPSCs in the co-culture system was studied, and the supernatant of YSCH-01/hDPSCs inhibited cell growth was further analyzed by CCK-8 assays.ResultshDPSCs were found to be susceptible to infection by a novel oncolytic adenovirus named YSCH-01 and were capable of transporting this virus to tumor sites at 1000 VP/cell infectious dosage in vitro and in vivo. Moreover, it was discovered that intraperitoneal injection of hDPSCs loaded with oncolytic adenovirus YSCH-01 exhibited potential anti-tumor effects in both SW780 and SCC152 xenograft models. The crucial role played by the supernatant secretome derived from hDPSCs loaded with YSCH-01 significantly exerted a specific anti-tumor effect without toxicity for normal cells, in both an active oncolytic virus and an exogenous protein-independent manner. Furthermore, the use of hDPSCs as a cell carrier significantly reduced the required dosage of virus delivery in vivo compared to other methods.ConclusionsThese findings highlight the promising clinical potential of hDPSCs as a novel cell carrier in the field of oncolytic virus-based anti-cancer therapy.

Dataset Information

Potent and specific antitumor effect for colorectal cancer by CEA and Rb double regulated oncolytic adenovirus harboring ST13 gene.

Publications

Potent and specific antitumor effect for colorectal cancer by CEA and Rb double regulated oncolytic adenovirus harboring ST13 gene.

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