mda-7/IL-24: Multifunctional cancer-specific apoptosis-inducing cytokine

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.

Enhanced delivery of mda-7/IL-24 using a serotype chimeric adenovirus (Ad.5/3) improves therapeutic efficacy in low CAR prostate cancer cells

“…[16][17][18] To engender an optimum therapeutic response using mda-7/IL-24, defining ways of ensuring efficient delivery of the molecule to the target cancer tissue would be helpful. By permitting virus entry in a CAR-independent manner, Ad.5/3 removes one important roadblock to effective in vivo delivery of therapeutic viruses.…”

“…10,11 This novel tumor suppressor cytokine is a member of the IL-10 gene family. [12][13][14][15][16][17] Forced expression of mda-7/IL-24, using Ad.5 (Ad.5-mda-7), inhibits growth and kills a broad spectrum of established cancer cell lines in vitro, without exerting injurious effects in multiple types of normal human epithelial cells, fibroblasts, melanocytes or astrocytes. [16][17][18][19][20][21] Considering its robust cancer-specific apoptosis-inducing ability (by inducing endoplasmic reticulum stress) and tumor growth-suppressing properties in nude mice human tumor xenograft models, Ad.mda-7 (INGN 241) was evaluated in a phase I clinical trial in patients with advanced cancers.…”

Enhanced antitumor activity by a selective conditionally replicating adenovirus combining with MDA-7/interleukin-24 for B-lymphoblastic leukemia via induction of apoptosis

“…Multiple signaling pathways have been shown to play a role in MDA-7/ IL-24-mediated apoptosis 45 including activation of PKR, 22 inhibition of b-catenin and PI3K, 46 activation of p38 MAPK, 23 upregulation of pro-apoptotic proteins 13,15 as well as downregulation of anti-apoptotic proteins. 47,48 Our preliminary data show that infection of leukemia cell line Mutz-1 with ZD55-IL-24 results in upregulation of PKR and also its downstream target phosphorylated p38 MAPK.…”

Targeting inhibition of K-ras enhances Ad.mda-7-induced growth suppression and apoptosis in mutant K-ras colorectal cancer cells

“…Multiple independent studies document that mda-7/IL-24 induces growth arrest and apoptosis in human cancer cell lines of diverse origin in vitro and inhibits human tumor xenograft growth in vivo in nude mice (reviewed by Fisher et al, 2003;Chada et al, 2004b;Fisher, 2005;Lebedeva et al, 2005a;Gupta et al, 2006;Sarkar et al, 2006). These studies also confirm that ectopic overexpression of mda-7/IL-24 does not affect growth or viability in normal cells.…”