title: MDA-7 (interleukin-24) inhibits the proliferation of renal carcinoma cells and interacts with free radicals to promote cell death and loss of reproductive capacity.
abstract: The median survival of metastatic renal cell carcinoma (RCC) is 12 months, and the majority of treatment options are palliative. MDA-7 (interleukin-24), when expressed via a recombinant replication defective adenovirus, Ad.mda-7, has profound antiproliferative and cytotoxic effects in a wide variety of tumor cells but not in nontransformed cells. The studies in this study examined the impact of MDA-7 on RCC proliferation and survival. RCC lines (A498 and UOK121N), but not primary renal epithelial cells, were resistant to adenoviral infection that correlated with a lack of coxsackievirus and adenovirus receptor expression. Additional studies were performed using purified preparations of bacterially synthesized glutathione S-transferase (GST)-MDA-7 protein. GST-MDA-7, but not GST, caused a dose-dependent inhibition of RCC proliferation but not of primary renal epithelial cells. Clinically achievable concentrations of the novel therapeutic agent arsenic trioxide (0.5-1 micro M) were found to have little effect on RCC growth. However, the combination of GST-MDA-7 and arsenic trioxide resulted in a greater than additive reduction in cell growth that correlated with a large increase in tumor cell death. The free radical scavenger N-acetyl cysteine abolished the potentiating effect of arsenic trioxide. Although pro-caspase 3, poly(ADP-ribose) polymerase, and Bcl-(XL) levels, as well as nucleosomal DNA integrity, were reduced by combined treatment, cell killing was predominantly nonapoptotic. Combined treatment of RCC lines with GST-MDA-7 and arsenic trioxide also resulted in a substantial reduction in clonogenic survival compared with either treatment individually. Collectively, these findings demonstrate that MDA-7 protein, in combination with agents that generate free radicals, may have potential in the treatment of RCC.
authors.affiliation: Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors.forename: Adly
authors.initials: A
authors.lastname: Yacoub
authors.forename: Clint
authors.initials: C
authors.lastname: Mitchell
authors.forename: Jessica
authors.initials: J
authors.lastname: Brannon
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rosenberg
authors.forename: Liang
authors.initials: L
authors.lastname: Qiao
authors.forename: Robert
authors.initials: R
authors.lastname: McKinstry
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Zao-shong
authors.initials: ZS
authors.lastname: Su
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Valerie
authors.forename: Rahul V
authors.initials: RV
authors.lastname: Gopalkrishnan
authors.forename: Steven
authors.initials: S
authors.lastname: Grant
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000256:Adenoviridae / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007378:Interleukins / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010087:Oxides / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011991:Receptors, Virus / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D000099180:Interleukin-24
chemical_list: D000111:Acetylcysteine; D000276:Adjuvants, Immunologic; D000077237:Arsenic Trioxide; D001152:Arsenicals; D020169:Caspases; D016166:Free Radical Scavengers; D005609:Free Radicals; D005982:Glutathione Transferase; D007378:Interleukins; D010087:Oxides; D011065:Poly(ADP-ribose) Polymerases; D019253:Proto-Oncogene Proteins c-bcl-2; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins; D051020:bcl-X Protein; D000099180:Interleukin-24; C494811:BCL2L1 protein, human