Targeted gene therapy for breast cancer with truncated Bid

Kazhdan, Irene; Long, Linda M; Montellano, Richard; Cavazos, David; Marciniak, Robert A.

doi:10.1038/sj.cgt.7700867

Cited by 20 publications

(20 citation statements)

References 41 publications

(40 reference statements)

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“…28,29 In this paradigm, only the Bid inhibitor, 13 but neither the 12/15-LOX inhibitors nor the radical scavenger Trolox, could prevent tBid toxicity. These data strongly suggest that activation of 12/15-LOX and formation of ROS initiated cell death mechanisms after glutamate treatment, whereas activation of Bid, mitochondrial damage and the boost of ROS are hallmarks of downstream mechanisms that cannot be blocked by 12/15-LOX inhibitors or radical scavengers.…”

Section: Discussionmentioning

confidence: 99%

“…This leads to Bid activation and mitochondrial damage followed by a second boost in ROS production and release of mitochondrial pro-apoptotic proteins such as AIF described. 29 For plasmid transfections 8 Â 10 4 HT-22 cells were seeded in 24-well plates. The antibiotic-containing growth medium was removed and replaced with 900 ml antibiotic-free growth medium.…”

Section: Methodsmentioning

confidence: 99%

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Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons

et al. 2010

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Glutamate toxicity involves increases in intracellular calcium levels and enhanced formation of reactive oxygen species (ROS) causing neuronal dysfunction and death in acute and chronic neurodegenerative disorders. The molecular mechanisms mediating glutamate-induced ROS formation are, however, still poorly defined. Using a model system that lacks glutamateoperated calcium channels, we demonstrate that glutamate-induced acceleration of ROS levels occurs in two steps and is initiated by lipoxygenases (LOXs) and then significantly accelerated through Bid-dependent mitochondrial damage. The Bid-mediated secondary boost of ROS formation downstream of LOX activity further involves mitochondrial fragmentation and release of mitochondrial apoptosis-inducing factor (AIF) to the nucleus. These data imply that the activation of Bid is an essential step in amplifying glutamate-induced formation of lipid peroxides to irreversible mitochondrial damage associated with further enhanced free radical formation and AIF-dependent execution of cell death. Cell Death and Differentiation (2011) 18, 282-292; doi:10.1038/cdd.2010.92; published online 6 August 2010Glutamate toxicity is a well-established cause for neuronal dysfunction and cell death in many acute and chronic neurological diseases. For example, increases in extracellular glutamate levels after acute brain damage by ischemic stroke, epilepsy or brain trauma may reach millimolar concentrations and induce massive Ca 2 þ influx and excitotoxic damage through activation of glutamate receptors such as N-methyl-D-aspartic acid (NMDA) receptors or a-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors. 1,2 The initial increase in intracellular Ca 2 þ levels after stimulation of these glutamate receptors is rather short and the following molecular mechanisms of glutamate excitotoxicity in neurons are poorly defined. While inhibition of the glutamate-induced Ca 2 þ influx by NMDA-receptor antagonists or antagonists of AMPA/kainate receptors protected neurons from glutamate excitotoxicity in experimental settings, the therapeutic time window of such neuroprotective effects is limited in vivo, and (post-)treatment strategies with glutamate receptor antagonists have failed in clinical studies to date. 3,4 Therefore, understanding the mechanisms of glutamate toxicity beyond the initial stimulation of Ca 2 þ influx is of utmost importance to provide efficient strategies of neuroprotection by targeting sustained mechanisms of glutamate-induced neuronal cell death. Such mechanisms include, for example, increased formation of reactive oxygen species (ROS), the activation of apoptosis-related death signaling, mitochondrial damage and DNA degradation.In particular, oxidative stress has been considered to cause neuronal dysfunction and cell death triggered by glutamate after acute brain injury and in age-related chronic neurodegenerative diseases. Therefore, recent research has focused on better understanding ROS formation and dissecting ROS-triggered neuronal death s...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Bid-mediated mitochondrial damage is a key mechanism in glutamate-induced oxidative stress and AIF-dependent cell death in immortalized HT-22 hippocampal neurons

et al. 2010

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“…2 In nonviral system using WT bax with various TSP failed to show significant activity in vitro. 23 We used several mutant forms of bax under the tumor-specific survivin promoter to test the efficacy of these nonviral vectors. Significantly increased activity of Sur-BaxWT could be achieved by the deletion mutation S184del in tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17][18][19] Although regulation of bax by hTERT promoter in an adenovirus vector has been shown to provide tumor-specific activity without hepatotoxicity, 2,20 the use of bax as a suicide gene in nonviral plasmid-based vectors has only been successful with cytomegalovirus (CMV) promoter 21,22 and not with TSPs. 23 Recent evidence has shown that bax apoptotic activity is regulated by translocation of cytoplasmic bax to the mitochondria under apoptotic stimuli. 12,24,25 This translocation is dependent on the conformational change in the C terminus of bax protein by dephosphorylation of serine at position 184 26 and possibly threonine at position 182.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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Suicide gene vectors are being developed in many laboratories as an attractive approach to cancer therapy. However, the development of these therapies is hampered by safety concerns and limitations of efficacy. The use of tumor-specific promoters, such as survivin promoter, can provide much needed specificity to target tumor cells. However, the expression levels from these promoters is often suboptimal and hence it is imperative to enhance the activity of the cytotoxic gene of interest. We tested apoptotic activity of several mutants of proapoptotic gene bax that constitutively translocate to the mitochondria and induce apoptosis. One of these mutants with deletion of serine at position S184 (S184del) was found to be most active and showed significant antitumor activity when expressed by the survivin promoter. In vitro testing shows that this vector (Sur-BaxS184del) induces cell killing in a variety of tumor cell lines of different origin with significantly higher efficacy than wild-type bax (SurBaxWT). The increase in cytotoxicity was a result of enhanced induction of apoptosis in tumor cells. In contrast to cytomegalovirus (CMV) promoter-driven bax (CMV-Bax), Sur-BaxS184del caused minimum toxicity in normal human dermal fibroblasts validating its specificity and safety. In a mouse tumor model (DA-3, murine breast cancer cells), we show that intratumoral injection of SurBaxS184del resulted in tumor growth retardation to the same level as CMV-Bax. This study highlights the effectiveness of using bax mutants in combination with survivin promoter for tumor-targeted suicide gene therapy in a nonviral vector.

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“…Breast cancer-targeted delivery systems are also constructed by modifying the envelop of viral particles, liposomes or other nanomaterials with tumor cellbinding phage peptides, or with ligands or antibodies that recognize HER2, E-selectin, transferrin or erythropoietin-producing hepatocellular receptor tyrosine kinase receptor class A2 (EphA2) (Alvarez et al, 2010;Mann et al, 2010;Normanno et al, 2009;Sarkar et al, 2005;Tandon et al, 2011). Tumor-specific regulatory elements, such as promoters of human telomerase reverse transcriptase (hTERT), survivin, Muc1 and the homologous recombinationrelated protein Rad51, as well as the hypoxia-responsive elements (HRE) have been employed in the regulation of pro-apoptotic genes like Bax and truncated Bid in the development of breast cancer-targeted therapeutic strategies (Lee, 2009;Kazhdan et al, 2006;Hine et al, 2008).…”

Section: Wwwintechopencommentioning

confidence: 99%