Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy

Li, Long-yuan; Dai, Huei-Yue; Yeh, Felix L.; Kan, Shu-Fen; Lang, Jing-Yu; Hsu, Jennifer L.; Jeng, Long-Bin; Chen, Ya‐Huey; Sher, Yuh‐Pyng; Lin, Wen‐Chuan; Hung, Mien‐Chie

doi:10.1038/onc.2010.558

Cited by 24 publications

(26 citation statements)

References 29 publications

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“…(8,10) Suicide gene therapy was effective in murine liver cancer models. (34,35) In addition, interleukin 12 treatment is able to suppress hepatocellular carcinoma in several mouse tumor models. (36,37) In the present study, we demonstrated that suppression of IDO in dendritic cells delayed tumor progression in subcutaneous, orthotopic and metastatic tumor models.…”

Section: Discussionmentioning

confidence: 99%

Skin delivery of short hairpin RNA of indoleamine 2,3 dioxygenase induces antitumor immunity against orthotopic and metastatic liver cancer

et al. 2011

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Liver cancer is one of the most malignant cancers in the world and has a high rate of metastasis. Therefore, development of a novel therapy for liver cancer is a critical issue. Indoleamine 2,3-dioxygenase (IDO) is known as a negative immune regulator in dendritic cells. Our previous study demonstrated that skin delivery of IDO short hairpin RNA (shRNA) induced antitumor immunity in subcutaneous bladder and colon tumor models. Because the immunological environment is quite different between skin and liver, it is essential to evaluate whether skin delivery of IDO shRNA is an effective treatment in metastatic and orthotopic animal tumor models. In the present study, IDO shRNA inhibited tumor growth in subcutaneous, metastatic and orthotopic liver tumor models. The cytotoxicity of splenocytes was significantly elevated in mice treated with IDO shRNA in the orthotopic and metastatic tumor models. Interleukin (IL)-12 and interferon (IFN)-gamma mRNA expression were upregulated while IL-10 was downregulated in the inguinal lymph nodes, which were collected from IDO shRNAtreated mice. Similar results were observed in the spleens of mice inoculated with IDO shRNA by gene gun. The results indicate that skin administration of IDO shRNA is an effective therapy in orthotopic and metastatic liver cancer animal models. Indoleamine 2,3-dioxygenase shRNA might be a potential new treatment for liver cancer in the future. (Cancer Sci 2011; 102: 2214-2220 L iver cancer is the fifth most common cancer in the world and the third leading cause of cancer-related death.(1,2) The incidence of liver cancer is still rising in the United States and some areas of Asia.(3) The 5-year survival rate of patients is relatively low and many patients die because of recurrence and metastasis.(4) In addition, advanced liver cancer has a poor response to radiotherapy and conventional chemotherapy. Treatment of 5-fluorouracil, adriamycin or doxorubicin provided little survival benefit.(7) Therefore, development of novel and effective therapeutic approaches is a critical issue in the management of liver cancer.An inhibitor of multi-targeted tyrosine kinase, sorafenib, was shown to increase the survival rate.(8) Other new drugs targeting vascular epithelial growth factor (VEGF), epithelial growth factor receptor (EGFR) or the mammalian target of rapamycin (mTOR) pathway are also being evaluated in several clinical studies.(9-11) Immunotherapy provides another kind of potential treatment for liver cancer. Some antigens including alphafetoprotein, SSX-2, MAGE-A and telomerase reverse transcriptase have been used to activate cytotoxic T cells against liver cancer.(12-15) The patients in the clinical trials showed partial or complete responses to various immunotherapies.(16) However, activation of immune cells in these studies usually requires time-consuming procedures ex vivo. Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme of the tryptophan metabolic pathway (17) and plays a negative role in immune regulation. Indoleamine 2,3-dioxygenaseexpress...

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Section: Discussionmentioning

confidence: 99%

Skin delivery of short hairpin RNA of indoleamine 2,3 dioxygenase induces antitumor immunity against orthotopic and metastatic liver cancer

et al. 2011

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“…Previous studies showed the presence of strong tissue-specific enhancer activity that is located upstream to the human AFP gene. The AFP enhancer is composed of two components, domain A (−4995 to −3744bp) and domain B (−3744 to −3330bp), both play important roles in up-regulating AFP promoter transcriptional activity in a tissue-specific manner [17,18]. The recombinant AFP transcription element containing AFP enhancer (−4995 to −3330bp) and basal promoter was constructed which showed transcription activity specific in HCC cells in our study.…”

Section: Discussionmentioning

confidence: 99%

“…As most tissue-specific promoters, AFP promoter has lower transcriptional activity. Previous studies showed the presence of an upstream transcriptional enhancer with strong tissue-specific activity, and transcriptional regulatory element containing this enhancer has been demonstrated to improve AFP promoter activity efficiently when being employed to target to HCC cells, limiting toxicity to surrounding normal cells [17,18]. …”

Section: Introductionmentioning

confidence: 99%

Cell-specific expression of artificial microRNAs targeting essential genes exhibit potent antitumor effect on hepatocellular carcinoma cells

et al. 2015

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To achieve specific and potent antitumor effect of hepatocyte carcinoma cells, replication defective adenoviral vectors, namely rAd/AFP-amiRG, rAd/AFP-amiRE and rAd/AFP-amiRP, were constructed which were armed with artificial microRNAs (amiRs) targeting essential functional genes glyceraldehyde-3-phosphate dehydrogenase, eukaryotic translation initiation factor 4E and DNA polymerase α respectively under the control of a recombinant promoter comprised of human α-fetoprotein enhancer and basal promoter. The AFP enhancer/promoter showed specific high transcription activity in AFP-positive HCC cells Hep3B, HepG2 and SMMC7721, while low in AFP-negative cell Bcap37. All artificial microRNAs exhibited efficient knockdown of target genes. Decreased ATP production and protein synthesis was observed in rAd/AFP-amiRG and rAd/AFP-amiRE treated HCC cells. All three recombinant adenoviruses showed efficient blockage of cell cycle progression and significant suppression of HCC cells in vitro. In nude mice model bearing Hep3B xenograft, administration of rAd/AFP-amiRG showed potent antitumor effect. The strategy of tumor-specific knockdown of genes essential for cell survival and proliferation may suggest a novel promising approach for HCC gene therapy.

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“…The endotoxin level was determined to be less than10 endotoxin units/mg of DNA (QCL-1000 kit, BioWhittaker). Plasmid was incorporated into extruded DOTAP/cholesterol liposome (29) that was produced in our laboratory according to the previously published protocol (30).…”

Section: Preparation Of Plasmids and Liposomementioning

confidence: 99%

Targeted Expression of BikDD Eliminates Breast Cancer with Virtually No Toxicity in Noninvasive Imaging Models

Xie

Xiao

et al. 2012

Molecular Cancer Therapeutics

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Breast cancer is a major public health problem all over the world, and the current treatment strategies are not potent enough for some patients, especially those with triple-negative breast cancer. Therefore, novel and more effective treatments are critically needed. Of the current methods, targeted therapy, which not only retains cancer-specific expression but also limits toxicity, is a new strategy for treating cancers. In this study, we found that the human telomerase reverse transcriptase (hTERT; T) promoter also possesses high target specificity in breast cancer. Moreover, we developed a versatile T-based breast cancer-specific promoter VISA (VP16-Gal4-WPRE integrated systemic amplifier) composite (T-VISA) to target transgene expression in breast tumors, which has stronger activity comparable or higher than that of the cytomegalovirus promoter in cancer cells. Thereafter, targeted expression of BikDD (a mutant form of proapoptotic gene Bik) through the T-VISA platform in breast cancer initiated robust antitumor effects and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of breast tumors with virtually no toxicity in intact mice. Thus, these findings show that our T-VISA-BikDD nanoparticles effectively and safely eradicate breast cancer in vitro and in vivo and are worthy of development in clinical trials treating breast cancer. Mol Cancer Ther; 11(9); 1915-24. Ó2012 AACR.

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Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy

Cited by 24 publications

References 29 publications

Skin delivery of short hairpin RNA of indoleamine 2,3 dioxygenase induces antitumor immunity against orthotopic and metastatic liver cancer

Skin delivery of short hairpin RNA of indoleamine 2,3 dioxygenase induces antitumor immunity against orthotopic and metastatic liver cancer

Cell-specific expression of artificial microRNAs targeting essential genes exhibit potent antitumor effect on hepatocellular carcinoma cells

Targeted Expression of BikDD Eliminates Breast Cancer with Virtually No Toxicity in Noninvasive Imaging Models

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