Swadesh K Das

Virginia Commonwealth University, Richmond, Virginia, United States

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Publications (60)313.51 Total impact

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    ABSTRACT: The oncogene AEG-1 (MTDH) is highly expressed in glioblastoma multiforme (GBM) and many other types of cancer, where it activates multiple signaling pathways that drive proliferation, invasion, angiogenesis, chemoresistance, radioresistance and metastasis. AEG-1 activates the Akt signaling pathway and Akt and c-Myc are positive regulators of AEG-1 transcription, generating a positive feedback loop between AEG-1 and Akt in regulating tumorigenesis. Here we describe in GBM cells a direct interaction between an internal domain of AEG-1 and the PH domain of Akt2, a major driver in GBM. Expression and interaction of AEG-1 and Akt2 are elevated in GBM and contribute to tumor cell survival, proliferation and invasion. Clinically, in silico gene expression and immunohistochemical analyses of patient specimens showed that AEG-1 and Akt2 expression correlated with GBM progression and reduced patient survival. AEG-1-Akt2 interaction prolonged stabilization of Akt2 phosphorylation at S474, regulating downstream signaling cascades which enable cell proliferation and survival. Disrupting AEG-1-Akt2 interaction by competitive binding of the Akt2-PH domain led to reduced cell viability and invasion. When combined with AEG-1 silencing, conditional expression of Akt2-PH markedly increased survival in an orthotopic mouse model of human GBM. Our study uncovers a novel molecular mechanism by which AEG-1 augments glioma progression and offers a rationale to block AEG-1-Akt2 signaling function as a novel GBM treatment.
    Cancer research. 10/2014;
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    ABSTRACT: Single drug therapies for cancer are often suboptimal and may not provide long term clinical benefits. To overcome this obstacle for effective treatment the applications of two or more drugs are preferable. A limitation of multidrug use is the varying pharmacokinetics of the different drugs. To overcome these impediments, we designed and synthesized multi-layered polyvinyl alcohol tethered hollow manganese ferrate nanocarriers capable of encapsulating two drugs with unique attributes of sensitivity towards tumor acidic milieu, mono-dispersive, compactness and high encapsulation efficiency. We encapsulated tamoxifen and diosgenin in peripheral and subsequent inner layers of multilayered nanocarriers. Characterizations revealed the size, surface charge, entrapment and controlled release. In vitro and in vivo studies evaluated nanocarrier uptake and retention ability of the tumor through magnetic saturation studies and elucidated the molecular mechanisms mediating drug(s)-induced apoptosis. The acidity of the tumor environment triggers extracellular dissociation of the peripheral coats resulting in release of tamoxifen blocking the estrogen receptor. The partially degraded nanocarriers localize intracellularly through endosomal escape and release diosgenin. Nanocarrier treatment reduced cellular levels of Bcl2 and p53, while increasing Bim. This delivery system successfully embodies sequential release of drugs and may provide a therapeutic strategy for sequentially affecting multiple targets in advanced cancers.
    Journal of Materials Chemistry 10/2014; · 5.97 Impact Factor
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    ABSTRACT: Introduction: Melanoma differentiation-associated gene - 9 (MDA-9)/Syntenin has become an increasingly popular focus for investigation in numerous cancertypes. Originally implicated in melanoma metastasis, it has diverse cellular roles and is consistently identified as a regulator of tumor invasion and angiogenesis. As a potential target for inhibiting some of the most lethal aspects of cancer progression, further insight into the function of MDA-9/Syntenin is mandatory. Areas covered: Recent literature and seminal articles were reviewed to summarize the latest collective understanding of MDA-9/Syntenin's role in normal and cancerous settings. Insights into its participation in developmental processes are included, as is the functional significance of the N- and C-terminals and PDZ domains of MDA-9/Syntenin. Current reports highlight the clinical significance of MDA-9/Syntenin expression level in a variety of cancers, often correlating directly with reduced patient survival. Also presented are assessments of roles of MDA-9/Syntenin in cancer progression as well as its functions as an intracellular adapter molecule. Expert opinion: Multiple studies demonstrate the importance of MDA-9/Syntenin in tumor invasion and progression. Through the use of novel drug design approaches, this protein may provide a worthwhile therapeutic target. As many conventional therapies do not address, or even enhance, tumor invasion, an anti-invasive approach would be a worthwhile addition in cancer therapy.
    Expert Opinion on Therapeutic Targets 09/2014; · 4.90 Impact Factor
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    ABSTRACT: Background Malignant glioma is an aggressive cancer requiring new therapeutic targets. MicroRNAs (miRNAs) regulate gene expression post transcriptionally and are implicated in cancer development and progression. Deregulated expressions of several miRNAs, specifically hsa-miR-184, correlate with glioma development. Methods Bioinformatic approaches were used to identify potential miR-184-regulated target genes involved in malignant glioma progression. This strategy identified a multifunctional nuclease, SND1, known to be overexpressed in multiple cancers, including breast, colon, and hepatocellular carcinoma, as a putative direct miR-184 target gene. SND1 levels were evaluated in patient tumor samples and human-derived cell lines. We analyzed invasion and signaling in vitro through SND1 gain-of-function and loss-of-function. An orthotopic xenograft model with primary glioma cells demonstrated a role of miR-184/SND1 in glioma pathogenesis in vivo. Results SND1 is highly expressed in human glioma tissue and inversely correlated with miR-184 expression. Transfection of glioma cells with a miR-184 mimic inhibited invasion, suppressed colony formation, and reduced anchorage-independent growth in soft agar. Similar phenotypes were evident when SND1 was knocked down with siRNA. Additionally, knockdown (KD) of SND1 induced senescence and improved the chemoresistant properties of malignant glioma cells. In an orthotopic xenograft model, KD of SND1 or transfection with a miR-184 mimic induced a less invasive tumor phenotype and significantly improved survival of tumor bearing mice. Conclusions Our study is the first to show a novel regulatory role of SND1, a direct target of miR-184, in glioma progression, suggesting that the miR-184/SND1 axis may be a useful diagnostic and therapeutic tool for malignant glioma.
    Neuro-Oncology 09/2014; · 6.18 Impact Factor
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    ABSTRACT: Polyinosine-polycytidylic acid (pIC) is a synthetic dsRNA that acts as an immune agonist of TLR3 and RLR to activate dendritic and NK cells that can kill tumor cells. pIC can also trigger apoptosis in pancreatic ductal adenocarcinoma cells but its mechanism of action is obscure. In this study, we investigated the potential therapeutic activity of a formulation of pIC with polyethylenimine ([pIC](PEI)) in PDAC and investigated its mechanism of action. [pIC](PEI) stimulated apoptosis in PDAC cells without affecting normal pancreatic epithelial cells. Mechanistically, [pIC](PEI) repressed XIAP and survivin expression and activated an immune response by inducing MDA-5, RIG-I and NOXA. Phosphorylation of AKT was inhibited by [pIC](PEI) in PDAC and this event was critical for stimulating apoptosis through XIAP and survivin degradation. In vivo administration of [pIC](PEI) inhibited tumor growth via AKT-mediated XIAP degradation in both subcutaneous and quasi-orthotopic models of PDAC. Taken together, these results offer a preclinical proof-of-concept for the evaluation of [pIC](PEI) as an immunochemotherapy to treat pancreatic cancer.
    Cancer research. 09/2014;
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    ABSTRACT: Gene therapy, which involves replacement of a defective gene with a functional, healthy copy of that gene, is a potentially beneficial cancer treatment approach particularly over chemotherapy, which often lacks selectivity and can cause non-specific toxicity. Despite significant progress pre-clinically with respect to both enhanced targeting and expression in a tumor-selective manner several hurdles still prevent success in the clinic, including non-specific expression, low-efficiency delivery and biosafety. Various innovative genetic approaches are under development to reconstruct vectors/transgenes to make them safer and more effective. Utilizing cutting-edge delivery technologies, gene expression can now be targeted in a tissue- and organ-specific manner. With these advances, gene therapy is poised to become amenable for routine cancer therapy with potential to elevate this methodology as a first line therapy for neoplastic diseases. This review discusses recent advances in gene therapy and their impact on a pre-clinical and clinical level. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 09/2014; · 4.22 Impact Factor
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    ABSTRACT: Human melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) displays potent growth suppressing and cell killing activity against a wide variety of human and rodent cancer cells. In this study, we identified a canine ortholog of the human mda-7/IL-24 gene located within a cluster of IL-10 family members on chromosome 7. The full-length mRNA sequence of canine mda-7 was determined, which encodes a 186-amino acid protein that has 66% similarity to human MDA-7/IL-24. Canine MDA-7 is constitutively expressed in cultured normal canine epidermal keratinocytes (NCEKs), and its expression levels are increased after lipopolysaccharide stimulation. In cultured NCEKs, the canine mda-7 pre-mRNA is differentially spliced, via exon skipping and alternate 5'-splice donor sites, to yield five splice variants (canine mda-7sv1, canine mda-7sv2, canine mda-7sv3, canine mda-7sv4 and canine mda-7sv5) that encode four protein isoforms of the canine MDA-7 protein. These protein isoforms have a conserved N-terminus (signal peptide sequence) and are dissimilar in amino acid sequences at their C-terminus. Canine MDA-7 is not expressed in primary canine tumor samples, and most tumor derived cancer cell lines tested, like its human counterpart. Unlike human MDA-7/IL-24, canine mda-7 mRNA is not expressed in unstimulated or lipopolysaccharide (LPS), concanavalin A (ConA) or phytohemagglutinin (PHA) stimulated canine peripheral blood mononuclear cells (PBMCs). Furthermore, in-silico analysis revealed that canonical canine MDA-7 has a potential 28 amino acid signal peptide sequence that can target it for active secretion. This data suggests that canine mda-7 is indeed an ortholog of human mda-7/IL-24, its protein product has high amino acid similarity to human MDA-7/IL-24 protein and it may possess similar biological properties to human MDA-7/IL-24, but its expression pattern is more restricted than its human ortholog.
    Gene 05/2014; · 2.20 Impact Factor
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    ABSTRACT: As a strategy to identify gene expression changes affected by human polynucleotide phosphorylase (hPNPaseold-35), we performed gene expression analysis of HeLa cells in which hPNPaseold-35 was overexpressed. The observed changes were then compared to those of HO-1 melanoma cells in which hPNPaseold-35 was stably knocked down. Through this analysis, 90 transcripts, which positively or negatively correlated with hPNPaseold-35 expression, were identified. The majority of these genes were associated with cell communication, cell cycle, and chromosomal organization gene ontology categories. For a number of these genes, the positive or negative correlations with hPNPaseold-35 expression were consistent with transcriptional data extracted from the TCGA (The Cancer Genome Atlas) expression datasets for colon adenocarcinoma (COAD), skin cutaneous melanoma (SKCM), ovarian serous cyst adenocarcinoma (OV), and prostate adenocarcinoma (PRAD). Further analysis comparing the gene expression changes between Ad.hPNPaseold-35 infected HO-1 melanoma cells and HeLa cells overexpressing hPNPaseold-35 under the control of a doxycycline-inducible promoter, revealed global changes in genes involved in cell cycle and mitosis. Overall, this study provides further evidence that hPNPaseold-35 is associated with global changes in cell cycle-associated genes and identifies potential gene targets for future investigation. J. Cell. Physiol. © 2014 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 04/2014; · 4.22 Impact Factor
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    ABSTRACT: Because of its overexpression in a range of solid tumors, the EphA2 receptor is a validated target for cancer therapeutics. We recently described a new targeted delivery system based on specific EphA2-targeting peptides conjugated with the chemotherapeutic agent paclitaxel. Here, we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel resulted in drug conjugates that are both long-lived in rat plasma and that markedly decrease tumor size in a prostate cancer xenograft model compared with paclitaxel alone treatment. These studies identify critical rate-limiting degradation sites on the peptide-drug conjugates, enabling the design of agents with increased stability and efficacy. These results provide support for our central hypothesis that peptide-drug conjugates targeting EphA2 represent an innovative and potentially effective strategy to selectively deliver cytotoxic drugs to cancer cells.
    ChemMedChem 03/2014; · 2.84 Impact Factor
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    ABSTRACT: Introduction: Melanoma is one of the most aggressive forms of cutaneous malignancies displaying a substantial mortality rate among the various forms of skin cancers. The management of patients with advanced melanoma poses a significant challenge considering that the disease is refractory to most conventional therapies. Areas covered: This review highlights some of the genes and signaling molecules that are mutated in melanoma patients. The authors also discuss protein kinase inhibitors targeting non-BRAF mutations that are now being evaluated in Phase II clinical trials. Expert opinion: In light of several preclinical and clinical studies, it is clear that targeting single-gene mutations may not provide a desired therapeutic gain in the context of melanoma. Consequently, research will need to focus on rational combinations of novel therapeutic agents targeting multiple genetic aberrations or deregulated pathways to achieve a desired maximum clinical benefit. There is certainly a need for a better understanding of the complex and redundant molecular signatures associated with melanoma development; this would open up new avenues for creating the next generation of targeted and effective therapeutics.
    Expert Opinion on Investigational Drugs 02/2014; · 4.74 Impact Factor
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    ABSTRACT: Elucidating the mechanism of pathogenesis of breast cancer has greatly benefited from breakthrough advances in both genetically engineered mouse (GEM) models and xenograft transplantation technologies. The vast array of breast cancer mouse models currently available is testimony to the complexity of mammary tumorigenesis and attempts by investigators to accurately portray the heterogeneity and intricacies of this disease. Distinct molecular changes that drive various aspects of tumorigenesis, such as alterations in tumor cell proliferation and apoptosis, invasion and metastasis, angiogenesis, and drug resistance have been evaluated using the currently available GEM breast cancer models. GEM breast cancer models are also being exploited to evaluate and validate the efficacy of novel therapeutics, vaccines, and imaging modalities for potential use in the clinic. This review provides a synopsis of the various GEM models that are expanding our knowledge of the nuances of breast cancer development and progression and can be instrumental in the development of novel prevention and therapeutic approaches for this disease.
    Advances in Cancer Research 01/2014; 121:331-82. · 6.35 Impact Factor
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    ABSTRACT: Despite an increased emphasis on developing new therapies for malignant gliomas, they remain among the most intractable tumors faced today as they demonstrate a remarkable ability to evade current treatment strategies. Numerous candidate treatments fail at late stages, often after showing promising preclinical results. This disconnect highlights the continued need for improved animal models of glioma, which can be used to both screen potential targets and authentically recapitulate the human condition. This review examines recent developments in the animal modeling of glioma, from more established rat models to intriguing new systems using Drosophila and zebrafish that set the stage for higher throughput studies of potentially useful targets. It also addresses the versatility of mouse modeling using newly developed techniques recreating human protocols and sophisticated genetically engineered approaches that aim to characterize the biology of gliomagenesis. The use of these and future models will elucidate both new targets and effective combination therapies that will impact on disease management.
    Advances in Cancer Research 01/2014; 121:261-330. · 6.35 Impact Factor
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    ABSTRACT: Molecular-genetic imaging of cancer using nonviral delivery systems has great potential for clinical application as a safe, efficient, noninvasive tool for visualization of various cellular processes including detection of cancer, and its attendant metastases. In recent years, significant effort has been expended in overcoming technical hurdles to enable clinical adoption of molecular-genetic imaging. This chapter will provide an introduction to the components of molecular-genetic imaging and recent advances on each component leading to safe, efficient clinical applications for detecting cancer. Combination with therapy, namely, generating molecular-genetic theranostic constructs, will provide further impetus for clinical translation of this promising technology.
    Advances in cancer research. 01/2014; 124:131-69.
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    ABSTRACT: Polynucleotide phosphorylase (PNPase) is an evolutionarily conserved 3'→5' phosphate-dependent exoribonucease belonging to the PDX family of proteins. It consists of two catalytic RNase PH domains (PNP1 and PNP2), an α-helical domain and two RNA-binding domains. The PNP1 and PNP2 domain share substantial sequence and structural homology with RNase PH (RPH), which is another PDX family member found in all the three major kingdoms of life, suggesting that these three domains originated from a common ancestor. Phylogenetic analysis (based on the PNPase/RNase PH sequence information for 43 vertebrate taxa) shows that PNP2 and RPH are sister taxa which arose through duplication of the ancestral PNP1 domain. Also, all three domains (PNP1, PNP2 and RPH), along with the KH and S1 domains have undergone significant and directional sequence change, as determined by branch and site-specific dN/dS analyses. In general, codons that show dN/dS ratios that are significantly greater than 1.0 are outside the ordered regions (α-helices and β-sheets) of these protein domains. In addition, sites that have been selected for mutagenesis in these proteins lie embedded in regions where there is a preponderance of codons with dN/dS values that are not significantly different from 0.0. Overall, this report is an attempt to further our understanding of the evolutionary history of these three protein domains, and define the evolutionary events that led to their refinement in the vertebrate lineage leading to mammals.
    Molecular Phylogenetics and Evolution 01/2014; · 4.07 Impact Factor
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    ABSTRACT: First identified almost two decades ago as a novel gene differentially expressed in human melanoma cells induced to terminally differentiate, MDA-7/IL-24 has since shown great potential as an anti-cancer gene. MDA-7/IL24, a secreted protein of the IL-10 family, functions as a cytokine at normal physiological levels and is expressed in tissues of the immune system. At supra-physiological levels, MDA-7/IL-24 plays a prominent role in inhibiting tumor growth, invasion, metastasis and angiogenesis and was recently shown to target tumor stem/initiating cells for death. Much of the attention focused on MDA-7/IL-24 originated from the fact that it can selectively induce cell death in cancer cells without affecting normal cells. Thus, this gene originally shown to be associated with melanoma cell differentiation has now proven to be a multi-functional protein affecting a broad array of cancers. Moreover, MDA-7/IL-24 has proven efficacious in a Phase I/II clinical trial in humans with multiple advanced cancers. As research in the field progresses, we will unravel more of the functions of MDA-7/IL-24 and define novel ways to utilize MDA-7/IL-24 in the treatment of cancer.
    Advances in experimental medicine and biology 01/2014; 818:127-53. · 1.83 Impact Factor
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    ABSTRACT: Background The extraordinary invasiveness of human glioblastoma multiforme (GBM) contributes to treatment failure and the grim prognosis of patients diagnosed with this tumor. Consequently, it is imperative to define further the cellular mechanisms that control GBM invasion and identify promising novel therapeutic targets. Melanoma differentiation associated gene-9 (MDA-9/syntenin) is a highly conserved PDZ domain-containing scaffolding protein that promotes invasion and metastasis in vitro and in vivo in human melanoma models. To determine whether MDA-9/syntenin is a relevant target in GBM, we investigated its expression in tumor samples and involvement in GBM invasion and angiogenesis.MaterialsWe assessed MDA-9/syntenin levels in available databases, patient tumor samples, and human-derived cell lines. Through gain-of-function and loss-of-function studies, we analyzed changes in invasion, angiogenesis, and signaling in vitro. We used orthotopic xenografts with GBM6 cells to demonstrate the role of MDA-9/syntenin in GBM pathogenesis in vivo.ResultsMDA-9/syntenin expression in high-grade astrocytomas is significantly higher than normal tissue counterparts. Forced overexpression of MDA-9/syntenin enhanced Matrigel invasion, while knockdown inhibited invasion, migration, and anchorage-independent growth in soft agar. Moreover, overexpression of MDA-9/syntenin increased activation of c-Src, p38 mitogen-activated protein kinase, and nuclear factor kappa-B, leading to elevated expression of matrix metalloproteinase 2 and secretion of interleukin-8 with corresponding changes observed upon knockdown. GBM6 cells that stably express small hairpin RNA for MDA-9/syntenin formed smaller tumors and had a less invasive phenotype in vivo.Conclusions Our findings indicate that MDA-9/syntenin is a novel and important mediator of invasion in GBM and a key regulator of pathogenesis, and we identify it as a potential target for anti-invasive treatment in human astrocytoma.
    Neuro-Oncology 12/2013; · 6.18 Impact Factor
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    ABSTRACT: Subtraction-hybridization combined with induction of cancer cell terminal differentiation in human melanoma cells identified melanoma differentiation associated gene-7 (mda-7/IL-24) and SARI (Suppressor of AP-1, induced by IFN) that display potent antitumor activity. These genes are not constitutively expressed in cancer cells and forced expression of mda-7/IL-24 (Ad.mda-7) or SARI (Ad.SARI) promotes cancer-specific cell death. Ectopic expression of mda-7/IL-24 induces SARI mRNA and protein in a panel of different cancer cells leading to cell death, without harming corresponding normal cells. Simultaneous inhibition of K-ras downstream extracellular regulated kinase 1/2 (ERK1/2) signaling in pancreatic cancer cells reverses the translational block of MDA-7/IL-24 and induces SARI expression and cell death. Using SARI-antisense-based approaches we demonstrate that SARI expression is necessary for mda-7/IL-24 antitumor effects. Secreted MDA-7/IL-24 protein induces antitumor 'bystander' effects by promoting its own expression. Recombinant MDA-7/IL-24 (His-MDA-7) induces SARI expression, supporting the involvement of SARI in the MDA-7/IL-24-driven autocrine loop culminating in antitumor effects. Moreover, His-MDA-7 after binding to its cognate receptors (IL-20R1/IL-20R2 or IL-22R/IL-20R2) induces intracellular signaling by phosphorylation of p38 MAPK leading to transcription of a family of growth arrest and DNA damage inducible (GADD) genes, culminating in apoptosis. Inhibition of p38 MAPK fails to induce SARI following Ad.mda-7 infection. These findings reveal the significance of the mda-7/IL-24-SARI axis in cancer-specific killing, and provide a potential strategy for treating both local and metastatic disease.
    Cancer Research 11/2013; · 9.28 Impact Factor
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    ABSTRACT: Conditionally replication competent adenoviruses (Ads) that selectively replicate in cancer cells and simultaneously express a therapeutic cytokine, such as melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24), a Cancer Terminator Virus (CTV-M7), hold potential for treating human cancers. To enhance the efficacy of the CTV-M7, we generated a chimeric Ad.5 and Ad.3 modified fiber bipartite CTV (Ad.5/3-CTV-M7) that can infect tumor cells in a Coxsackie Adenovirus receptor (CAR) independent manner, while retaining high infectivity in cancer cells containing high CAR. Although mda-7/IL-24 displays broad-spectrum anticancer properties, pancreatic ductal adenocarcinoma (PDAC) cells display an intrinsic resistance to mda-7/IL-24-mediated killing due to an mda-7/IL-24 mRNA translational block. However, using a chemoprevention gene therapy (CGT) approach with perillyl alcohol (POH) and a replication incompetent Ad to deliver mda-7/IL-24 (Ad.mda-7) there is enhanced conversion of mda-7/IL-24 mRNA into protein resulting in pancreatic cancer cell death in vitro and in vivo in nude mice containing human PDAC xenografts. This combination synergistically induces mda-7/IL-24-mediated cancer-specific apoptosis by inhibiting anti-apoptotic Bcl-xL and Bcl-2 protein expression and inducing an endoplasmic reticulum (ER) stress response through induction of BiP/GRP-78, which is most evident in chimeric-modified non-replicating Ad.5/3-mda-7- and CTV-M7-infected PDAC cells. Moreover, Ad.5/3-CTV-M7 in combination with POH sensitizes therapy-resistant MIA PaCa-2 cell lines over-expressing either Bcl-2 or Bcl-xL to mda-7/IL-24-mediated apoptosis. Ad.5/3-CTV-M7 plus POH also exerts a significant antitumor 'bystander' effect in vivo suppressing both primary and distant site tumor growth, confirming therapeutic utility of Ad.5/3-CTV-M7 plus POH in PDAC treatment, where all other current treatment strategies in clinical settings show minimal efficacy.
    Current Molecular Medicine 11/2013; · 4.20 Impact Factor
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    ABSTRACT: In the present study we show that histone deacetylase inhibitors (HDACIs) enhance the anti-tumor effects of melanoma differentiation associated gene-7/interleukin 24 (mda- 7/IL-24) in human renal carcinoma cells. Similar data were obtained in other GU tumor cells. Combination of these two agents resulted in increased autophagy that was dependent on expression of ceramide synthase 6, with HDACIs enhancing MDA-7/IL-24 toxicity by increasing generation of ROS and Ca (2+). Knock down of CD95 protected cells from HDACI and MDA-7/IL-24 lethality. Sorafenib treatment further enhanced (HDACI + MDA-7/IL-24) lethality. Anoikis resistant renal carcinoma cells were more sensitive to MDA-7/IL-24 that correlated with elevated SRC activity and tyrosine phosphorylation of CD95. We employed a recently constructed serotype 5/3 adenovirus, which is more effective than a serotype 5 virus in delivering mda- 7/IL-24 to renal carcinoma cells and which conditionally replicates (CR) in tumor cells expressing MDA-7/IL-24 by virtue of placing the adenoviral E1A gene under the control of the cancer-specific promoter progression elevated gene-3 (Ad.5/3-PEG-E1A-mda-7; CRAd.5/3-mda-7, Ad.5/3-CTV), to define efficacy in renal carcinoma cells. Ad.5/3-CTV decreased the growth of renal carcinoma tumors to a significantly greater extent than did a non-replicative virus Ad.5/3-mda-7. In contralateral uninfected renal carcinoma tumors Ad.5/3-CTV also decreased the growth of tumors to a greater extent than did Ad.5/3-mda-7. In summation, our data demonstrates that HDACIs enhance MDA-7/IL-24-mediated toxicity and tumor specific adenoviral delivery and viral replication of mda-7/IL-24 is an effective pre-clinical renal carcinoma therapeutic.
    Cancer biology & therapy 08/2013; 14(11). · 3.29 Impact Factor
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    ABSTRACT: Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression. Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knock down was examined in multiple cells lines and key findings were validated in primary tumors. Significantly higher (p= 0.002-0.003) expression of MDA-9/Syntenin was observed in 64% (28/44) of primary tumors and an association was evident with stage (p=0.01), grade (p=0.03) and invasion status (p=0.02). MDA-9/Syntenin overexpression in non-tumorigenic HUC-1 cells increased proliferation (p=0.0012), invasion (p=0.0001) and EGFR, AKT, PI3K and c-Src expression. Alteration of Beta-catenin, E-Cadherin, Vimentin, Claudin-1, ZO-1 and TCF4 expression were also observed. MDA-9/Syntenin knock down in 3 UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and co-localization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin:AKT expressions with stage (p=0.04, EGFR), (p=0.01, AKT). A correlation between MDA-9/Syntenin:ß-catenin co-expression with stage (p=0.03) and invasion (p=0.04) was also evident. Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring and therapeutic strategies for managing UCC.
    Clinical Cancer Research 07/2013; · 7.84 Impact Factor

Publication Stats

430 Citations
313.51 Total Impact Points

Institutions

  • 2010–2014
    • Virginia Commonwealth University
      • Department of Human and Molecular Genetics
      Richmond, Virginia, United States
  • 2013
    • IIT Kharagpur
      • Department of Medical Science and Technology
      Kharagpur, Bengal, India
    • National Institute of Technology Rourkela
      • Department of Life Science (LS)
      Sundergarh, Orissa, India
  • 2012
    • PSG Institute of Advanced Studies
      Koyambattūr, Tamil Nādu, India
    • Richmond VA Medical Center
      Richmond, Virginia, United States
  • 2011
    • Kyung Hee University
      • Institute of Oriental Medicine
      Seoul, Seoul, South Korea