@article{809d03916787424eba68c74af93efa28,
title = "Enhancing mda-7/IL-24 therapy in renal carcinoma cells by inhibiting multiple protective signaling pathways using sorafenib and by Ad.5/3 gene delivery",
abstract = "We have determined whether an adenovirus that comprises the tail and shaft domains of a serotype 5 virus and the knob domain of a serotype 3 virus expressing MDA-7/IL-24, Ad.5/3-mda-7, more effectively infects and kills renal carcinoma cells (RCCs) compared to a serotype 5 virus, Ad.5-mda-7. RCCs are a tumor cell type that generally does not express the receptor for the type 5 adenovirus; the coxsakie and adenovirus receptor (CAR). Ad.5/3-mda-7 infected RCCs to a much greater degree than Ad.5-mda-7. MDA-7/IL-24 protein secreted from Ad.5/3-mda-7-infected RCCs induced MDA-7/IL-24 expression and promoted apoptosis in uninfected {"}bystander{"} RCCs. MDA-7/IL-24 killed both infected and bystander RCCs via CD95 activation. Knockdown of intracellular MDA-7/IL-24 in uninfected RCCs blocked the lethal effects of conditioned media. Infection of RCC tumors in one flank, with Ad.5/3-mda-7, suppressed growth of infected tumors and reduced the growth rate of uninfected tumors implanted on the opposite flank. The toxicity of the serotype 5/3 recombinant adenovirus to express MDA-7/IL-24 was enhanced by combined molecular or small molecule inhibition of MEK1/2 and PI3K; inhibition of mTOR, PI3K and MEK1/2; or use of the multi-kinase inhibitor sorafenib. In RCCs, combined inhibition of cytoprotective cell signaling pathways enhanced the MDA-7/IL-24-induction of CD95 activation, with greater mitochondrial dysfunction due to loss of MCL-1 and BCL-XL expression and tumor cell death. Treatment of RCC tumors in vivo with sorafenib also enhanced Ad.5/3-mda-7 toxicity and prolonged animal survival. Future combinations of these approaches hold promise for developing a more effective therapy for kidney cancer.",
keywords = "AKT, ERK, Interleukin, JNK, Kidney, MAPK, MDA-7/IL-24, PERK, PI3K, RCC, Sorafenib",
author = "Eulitt, {Patrick J.} and Park, {Margaret A.} and Hamed, {Hossein A.} and Nichola Cruikshanks and Chen Yang and Dmitriev, {Igor P.} and Adly Yacoub and Curiel, {David T.} and Fisher, {Paul B.} and Paul Dent",
note = "Funding Information: were permitted to form over the following month. Adenoviral vec-Support for the present study was provided: to P.D. from PHS tors, Ad.5/3-mda-7 or Ad.5/3-cmv were administered ~1 month grants (P01-CA104177, R01-CA108520, R01-DK52825; after tumor cell implantation into animals. Viral vectors (Ad.5/3-R01-CA141703; R01-CA150214), The Jim Valvano “V” founda-mda-7 or Ad.cmv, 1 x 109 p.f.u.) suspended in 2 μl of PBS were tion and Department of Defense Award (W81XWH-10-1-0009); delivered by slow infusion over a 6 min period. to P.B.F. from PHS grants (P01-CA104177, R01-CA097318; Immunohistochemistry and staining of fixed tumor sections. Post-R01-CA127641; R01-CA134721; R01-CA108520), the Samuel sacrifice, tumors wer{\"U}e fixed in OCT compo-undB (TOissueE TekF); TWax#man JCPancTer RDeseJarFch OFounDdaFtion (SWCRF) and the cryostat sectioned (Leica) as 12 μm sections. Nonspecific bind-National Foundation for Cancer Research (NFCR); to D.T.C. ing was blocked with a 2% (v/v) R%at Sera, 1% (v/v)m Bovine from PHS grant (P01-CA104177). P.D. is The Universal Inc., Sera, 0.1% (v/v) Triton X100, 0.05% (vP/v) TOweenP-20 sUoluEtionJTProUfesSsor iJCn SVignalU TFransduction Research. PBF holds the then sections were stained for cell signaling pathway markers: Thelma Newmeyer Corman Chair in Cancer Research at the Animals that received recombinant adenoviruses were moni-VCU Massey Cancer Center, VCU, School of Medicine and is a tored twice weekly for survival or signs of disease. Other animals SWCRF Investigator.",
year = "2010",
month = dec,
day = "15",
doi = "10.4161/cbt.10.12.13497",
language = "English",
volume = "10",
pages = "1290--1305",
journal = "Cancer Biology and Therapy",
issn = "1538-4047",
number = "12",
}