Improved nonviral cancer suicide gene therapy using survivin promoter-driven mutant Bax

Garg, Himanshu; Salcedo, Rosalba; Trinchieri, Georgio; Blumenthal, Robert

doi:10.1038/cgt.2009.63

Cited by 27 publications

(20 citation statements)

References 28 publications

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“…The survivin promoter was superior to other promoters, additionally it exhibited very low activities in major organs [40]. It mediated genes targeted therapy that had been detected in breast cancer [26], lung cancer [41][42] , gastric cancer [43] and glioma [40].…”

Section: Discussionmentioning

confidence: 99%

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Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

Wang

Zhou²,

Li³

et al. 2013

neo

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Hepatocellular carcinoma (HCC) is one of the most common types of cancer worldwide. However, there is currently no effective therapy strategy in the clinical practice. Recombinant phytotoxin gelonin fused to other factors have been used to treat different cancers. But there have been no reports of gelonin gene therapy. In this study, we have constructed a recombinant plasmid which contained a tumor-specific survivin promoter to drive phytotoxin gelonin (pSur-Gel). And the cytotoxicity effects of pSur-Gel in HCC were also validated both in vitro and in vivo. The expression level of survivin was detetected in different liver cancer cell lines and nomal liver cell lines by western blot analysis, and a survivin promoter-driven green fluorescent protein (GFP) expression vectors (pSur-GFP) was also tested in liver cancer cell line HepG2 and normal liver cell line LO2. Moreover, phytotoxin gelonin expression experiment and cytotoxicity experiment of pSur-Gel was performed in HepG2 cells and LO2 cells in vitro. Furthermore, anti-tumor effect of pSur-Gel against HepG2 xenografts and toxicity of this gene were evaluated in the mice model. Finally, LDH release assay, apoptosis assay and immunoblot analyse LC3 conversion (LC3-I to LC3-II) were tested. We found that the expression of survivin protein was higher in liver cancer cell lines compared with the normal liver cells. Further study showed that the pSur-GFP and pSur-Gel was expressed specially in liver cancer cell other than in normal liver cells. pSur-Gel plasmid could effectively inhibit the proliferation of liver cancer cells (*P<0.05), and significantly repress the growth of HepG2 xenografts via intravenous in vivo (*P<0.05). Otherwise, compared to cytomegalovirus promoter-driven gelonin expression vectors (pCMV-Gel), no significantly systemic toxicity or organ injuries had been observed in pSur-Gel treated mice. Further studies revealed that the phytotoxin gelonin induced cell death might be mediated by apoptosis and the damage of cell membrane. Taken together, treating hepatocellular carcinoma with the pSur-Gel may be a novel and interesting cancer gene therapy protocol and is worthy of further development for future clinical trials.

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Section: Discussionmentioning

confidence: 99%

“…Numerous researches have validated the specificity and utility of survivin promoter for tumor targeting therapy [26]. Survivin is over-expressed in common cancers, but not in normal adult tissues [27][28][29].…”

mentioning

confidence: 99%

Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

Wang

Zhou²,

Li³

et al. 2013

neo

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“…Plasmids pGL3-T-Luc, pGL3-Survivin-Luc, pGL3-Clandin-4-Luc, pGL3-FASN-Luc, pGL3-b-cateinin-Luc, and pGL3-CMV-Luc containing the T, survivin, claudin-4, FASN, b-catenin, and CMV promoter, respectively, to drive the expression of the firefly luciferase gene were previously described (14,15,19,21,26). The VISA amplification system was incorporated into the pGL3-T-Luc plasmid to create pGL3-T-VISA-Luc.…”

Section: Preparation Of Plasmids and Liposomementioning

confidence: 99%

“…17,18), survivin (19,20), claudin-4 (21-23), fatty acid synthase (FASN; refs. 24,25), and b-catenin (26).…”

Section: Introductionmentioning

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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“…The limitation of expression of killer genes in tumor cells is one of these challenges. One of the applied solutions is the use of specific promoters of tissue and tumor like human telomerase reverse transcriptase (5) and Survivin (6). However, the main problem of these promoters is their low efficiency.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Response Elements Can Cause the Overexpression of the BAX mRNA Under Hypoxic Condition

2016

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Background: Suicide gene therapy is one of the modern methods of cancer treatment. However, transmission for tumor cells is one of the main challenges to overcome. Hypoxia is a common phenomenon in solid tumors that lead to changes in tumors microenvironment. Hypoxia-responsive element sequences are regulatory sequences that lead to activation of their upstream and downstream genes in hypoxic time. Bax is a strong proapoptotic gene that causes apoptosis in the time of over expression in cells. Objectives: The aim of this study is to use this sequence in order to specify suicide gene therapy by the help of a gene producing Bax protein under control of CMV promoter. Methods: The gene of BAX, BAX3HRE and 3HRE were cloned into interested vectors. In the next step, the function of HRE sequence on over expression of upstream gene under hypoxic condition was evaluated through western blot, MTT assay and real time PCR. Results: The results of this study indicate that cells transected by pcDNA3.1/BAX 3HRE. The rate of apoptosis in them significantly increased in comparison with pcDNA3.1/BAX in hypoxic conditions. Conclusions: Regarding the role of HREs in increasing the expression of its upstream genes, it can be used to specify suicide gene therapy in treatment of solid tumors.

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Improved nonviral cancer suicide gene therapy using survivin promoter-driven mutant Bax

Cited by 27 publications

References 28 publications

Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

Suppression of hepatoma tumor growth by systemic administration of the phytotoxin gelonin driven by the survivin promoter

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

Hypoxia Response Elements Can Cause the Overexpression of the BAX mRNA Under Hypoxic Condition

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