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: 9.72). 10/2006; 111(3):596-628. DOI: 10.1016/j.pharmthera.2005.11.005
Source: PubMed


"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
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    • "The apoptotic pathways by which MDA-7/IL-24 kills tumor cells remain to be fully understood; however, current evidence suggests an inherently high degree of complexity and an involvement of proteins important for the onset of growth inhibition and apoptosis, including Bcl-XL, Bcl-2 and Bax (3,4,14,17,23–25). MDA-7 has also been shown to influence endothelial cells, exerting a potentially antiangiogenic effect within the tumor vasculature (26). "
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    ABSTRACT: The melanoma differentiation-associated gene-7 [MDA-7; renamed interleukin (IL)-24] was isolated from human melanoma cells induced to terminally differentiate by treatment with interferon and mezerein. MDA-7/IL-24 functions as a multimodality anticancer agent, possessing proapoptotic, antiangiogenic and immunostimulatory properties. All these attributes make MDA-7/IL-24 an ideal candidate for cancer gene therapy. In the present study, the human MDA-7/IL-24 gene was transfected into the human laryngeal cancer Hep-2 cell line and human umbilical vein endothelial cells (HUVECs) with a replication-incompetent adenovirus vector. Reverse transcription polymerase chain reaction and western blot analysis confirmed that the Ad-hIL-24 was expressed in the two cells. The expression of the antiapoptotic gene, Bcl-2, was significantly decreased and the IL-24 receptor was markedly expressed in Hep-2 cells following infection with Ad-hIL-24, but not in HUVECs. In addition, the expression of the proapoptotic gene, Bax, was induced and the expression of caspase-3 was increased in the Hep-2 cells and HUVECs. Methyl thiazolyl tetrazolium assay indicated that Ad-hIL-24 may induce growth suppression in Hep-2 cells but not in HUVECs. In conclusion, Ad-hIL-24 selectively inhibits proliferation and induces apoptosis in Hep-2 cells. No visible damage was found in HUVECs. Therefore, the results of the current study indicated that Ad-hIL-24 may have a potent suppressive effect on human laryngeal carcinoma cell lines, but is safe for healthy cells.
    Full-text · Article · Mar 2014 · Oncology letters
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    • "The 3′-untranslated region (UTR) of IL-24 mRNA has three consensus elements (AUUUA) and three polyadenylation signals (AAUAAA) which is involved in mRNA stability and regulation respectively [1,6]. Sequence analysis of IL-24 showed that it has an N-terminal hydrophobic signal peptide of 49 amino-acid in length that allows the IL-24 protein to be cleaved and secreted [7]. IL-24 has five phosphorylation (Serine 88, 101 & 161 and Threonine-111 &133) and three glycosylation sites (Cysteine 95, 109 and 126) [8,9]. "
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    ABSTRACT: Cancer remains a major health issue in the world and the effectiveness of current therapies is limited resulting in disease recurrence and resistance to therapy. Therefore to overcome disease recurrence and have improved treatment efficacy there is a continued effort to develop and test new anticancer drugs that are natural or synthetic - (conventional chemotherapeutics, small molecule inhibitors) and biologic (antibody, tumor suppressor genes, oligonucleotide) product. In parallel, efforts for identifying molecular targets and signaling pathways to which cancer cells are “addicted” are underway. By inhibiting critical signaling pathways that is crucial for cancer cell survival, it is expected that the cancer cells will undergo a withdrawal symptom akin to “de-addiction” resulting in cell death. Thus, the key for having an improved and greater control on tumor growth and metastasis is to develop a therapeutic that is able to kill tumor cells efficiently by modulating critical signaling pathways on which cancer cells rely for their survival. Currently several small molecule inhibitors targeted towards unique molecular signaling pathways have been developed and tested in the clinic. Few of these inhibitors have shown efficacy while others have failed. Thus, targeting a single molecule or pathway may be insufficient to completely block cancer cell proliferation and survival. It is therefore important to identify and test an anticancer drug that can inhibit multiple signaling pathways in a cancer cell, control growth of both primary and metastatic tumors and is safe. One biologic agent that has the characteristics of serving as a potent anticancer drug is interleukin (IL)-24. IL-24 suppresses multiple signaling pathways in a broad-spectrum of human cancer cells leading to tumor cell death, inhibition of tumor angiogenesis and metastasis. Additionally, combining IL-24 with other therapies demonstrated additive to synergistic antitumor activity. Clinical testing of IL-24 as a gene-based therapeutic for the treatment of solid tumors demonstrated that IL-24 is efficacious and is safe. The unique features of IL-24 support its further development as an anticancer drug for cancer treatment. In this review we summarize the current understanding on the molecular targets and signaling pathways regulated by IL-24 in mediating its anticancer activity.
    Full-text · Article · Dec 2013 · Journal of Molecular Signaling
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    • "IL-24 is a good candidate for expression by OVs, as it is an effective antiangiogenic cytokine and as well, induces apoptosis and reduced growth in many tumors.70,71 Three different oncolytic adenoviruses have been engineered to express IL-24,72–74 with coexpression of arrestin, and these were effective in a melanoma model.74 "
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    ABSTRACT: Oncolytic viruses (OVs) have the ability to selectively replicate in and lyse cancer cells. Angiogenesis is an essential requirement for tumor growth. Like OVs, the therapeutic effect of many angiogenesis inhibitors has been limited, leading to the development of more effective approaches to combine antiangiogenic therapy with OVs. Angiogenesis can be targeted either directly by OV infection of vascular endothelial cells, or by arming OVs with antiangiogenic transgenes, which are subsequently expressed locally in the tumor microenvironment. In this review, we describe the development and targeting of OVs, the role of angiogenesis in cancer, and the progress made in arming viruses with antiangiogenic transgenes. Future developments required to optimize this approach are addressed.
    Full-text · Article · Jul 2013 · OncoTargets and Therapy
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