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Gupta, P, Su, ZZ, Lebedeva, IV, Sarkar, D, Sauane, M, Emdad, L et al.. mda-7/IL-24: multifunctional cancer-specific apoptosis-inducing cytokine. Pharmacol Ther 111: 596-628

Columbia University, New York, New York, United States
Pharmacology [?] Therapeutics (Impact Factor: 7.75). 10/2006; 111(3):596-628. DOI: 10.1016/j.pharmthera.2005.11.005
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ABSTRACT "Differentiation therapy" provides a unique and potentially effective, less toxic treatment paradigm for cancer. Moreover, combining "differentiation therapy" with molecular approaches presents an unparalleled opportunity to identify and clone genes mediating cancer growth control, differentiation, senescence, and programmed cell death (apoptosis). Subtraction hybridization applied to human melanoma cells induced to terminally differentiate by treatment with fibroblast interferon (IFN-beta) plus mezerein (MEZ) permitted cloning of melanoma differentiation associated (mda) genes. Founded on its novel properties, one particular mda gene, mda-7, now classified as a member of the interleukin (IL)-10 gene family (IL-24) because of conserved structure, chromosomal location, and cytokine-like properties has become the focus of attention of multiple laboratories. When administered by transfection or adenovirus-transduction into a spectrum of tumor cell types, melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) induces apoptosis, whereas no toxicity is apparent in normal cells. mda-7/IL-24 displays potent "bystander antitumor" activity and also has the capacity to enhance radiation lethality, to induce immune-regulatory activities, and to inhibit tumor angiogenesis. Based on these remarkable attributes and effective antitumor therapy in animal models, this cytokine has taken the important step of entering the clinic. In a Phase I clinical trial, intratumoral injections of adenovirus-administered mda-7/IL-24 (Ad.mda-7) was safe, elicited tumor-regulatory and immune-activating processes, and provided clinically significant activity. This review highlights our current understanding of the diverse activities and properties of this novel cytokine, with potential to become a prominent gene therapy for cancer.

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Available from: Irina V Lebedeva, Aug 25, 2015
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    • "Although IL-24 exhibits interesting properties through various signaling pathways [8] [9] [10] [11] [12] [13] [14] [15] [16], the molecular mechanisms involved in the regulation of IL-24 expression and activation and its anticancer activity are not yet completely understood [17] [18]. Recombinant IL-24 induces apoptosis in a broad range of human cancers including colorectal cancer (CRC), with no significant toxicity to normal cells [19]. In addition, IL-24 inhibits angiogenesis, stimulates antitumor immune response, sensitizes cancer cells to radiation and other modalities of conventional therapies, and induces multipronged 'bystander' activity eliminating both primary and distant tumors in animal models [20] [21]. "
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    ABSTRACT: Colon cancer is one of the most commonly diagnosed cancers in the United States. Recombinant MDA-7/IL-24 has showed its selective cytotoxicity against cancer cells, and Ad-mda7 (INGN-241) is currently under clinical investigation for solid tumors. Here, we investigated the expression of MDA-7/IL-24 in colorectal cancer (CRC) tissues from 202 patients. Compared with the adjacent mucosa, CRC tissues displayed significantly lower MDA-7/IL-24 levels. The MDA-7/IL-24 levels in CRC were significantly associated with patients' survival rate in a 6-year period. These results indicate MDA-7/IL-24 level is both a diagnostic and prognostic biomarker for CRC, and support the role of MDA-7/IL-24 in the treatment of CRC. To elevate MDA-7/IL-24 level for colon cancer treatment, we successfully developed a small-molecule compound SC144 with the ability to up-regulate MDA-7/IL-24 expression via direct binding to and stabilizing MDA-7/IL-24 in human colon cancer cells. Among the analogues tested, SC144 exhibited the highest cytotoxicity in a panel of colon cancer cell lines in a p53-independent manner, accompanied by cell cycle arrest in G0/G1 with downregulation of Cyclin D1 levels, and apoptosis induction with upregulation of cell surface-bound Fas/CD95. These results combined with our previous studies support the anticancer role of MDA-7/IL-24 as well as the clinical development of SC144 for colon cancer treatment.
    Cancer letters 03/2013; 335(2). DOI:10.1016/j.canlet.2013.02.055 · 5.62 Impact Factor
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    • "In this study, AdvGFP/ MDA-7 was demonstrated to induce apoptosis of HepG2 cells in vitro. Treatment of HepG2 cells with AdvGFP/MDA-7, but not AdvGFP or PBS, resulted in a significant reduction in the number of cells in the S phase concomitant with an increase in the number of cells in the G2/M phase, which was consistent with findings of a previous study [13] . "
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    ABSTRACT: Hepatocellular carcinoma is one of the most common tumors in the world. The purpose of the present study was to investigate the inhibitory effects of adenoviral transduction of human melanoma differentiation-associated gene-7 (MDA-7) gene on hepatocellular carcinoma, so as to provide a theoretical basis for gene therapy of the disease. The human MDA-7 gene was cloned into replication-defective adenovirus specific to HepG2 cells using recombinant virus technology. RT-PCR and Western blotting assays were used to determine the expression of human MDA-7 mRNA and MDA-7 protein in HepG2 cells in vitro. Induction of apoptosis by overexpression of the human MDA-7 gene was determined by flow cytometry. In-vivo efficacy of adenoviral delivery of the human MDA-7 gene was assessed in nude mice bearing HepG2 cell lines in vivo by determining inhibition of tumor growth, VEGF and CD34 expression, and microvascular density (MVD). The results showed that AdGFP/MDA-7 induced apoptosis of HepG2 cells in vitro and significantly inhibited tumor growth in vivo (P < 0.05). The intratumoral MVD decreased significantly in the treated tumors (P < 0.05). We conclude the recombination adenovirus AdGFP/MDA-7 can effectively express biologically active human MDA-7, which leads to inhibition of hepatocellular carcinoma growth.
    01/2012; 26(1):53-8. DOI:10.1016/S1674-8301(12)60007-4
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    • "The receptors for IL-24 expressed by endothelial cells, IL-20R2/IL- 20R1 and IL-20R2/IL-22R, are know to signal through the JAK/STAT pathway activation [8] [11] [12] [30]. We therefore tested inhibitors of these pathways and found that MEK, hatched bars compared to solid bars, (Fig. 3B) and JAK, hatched bars compared to solid bars, (Fig. 3C) inhibitors significantly decrease monocyte migration induced by IL-24. "
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    ABSTRACT: IL-24 (melanoma differentiation associated gene 7 product) is a member of the IL-10 cytokine family that has been reported to possess anti-tumor activity. IL-24 is produced by immune tissues and its expression can be induced in human peripheral blood mononuclear cells by pathogen-associated molecules. While immune cells are known to produce IL-24, the response of immune cells to IL-24 is unclear. Using recombinant human IL-24, we demonstrated that IL-24 induces human monocyte and neutrophil migration, in vitro. An in vivo chemotaxis model showed that IL-24 attracted CD11b positive myeloid cells. To further characterize the chemotactic IL-24 response and type(s) of receptor(s) utilized by IL-24, we treated monocytes with signaling pathway inhibitors. IL-24-induced migration was reduced by pertussis toxin treatment, thus implicating G-protein coupled receptors in this process. Additionally, MEK and JAK inhibitors markedly decreased monocyte migration toward IL-24. These results suggest that IL-24 activates several signaling cascades in immune cells eliciting migration of myeloid cells, which may contribute to the known anti-cancer effects of IL-24.
    Cytokine 06/2011; 55(3):429-34. DOI:10.1016/j.cyto.2011.05.018 · 2.87 Impact Factor
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