Journal
CANCER BIOLOGY & THERAPY
Volume 10, Issue 12, Pages 1290-1305Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.10.12.13497
Keywords
ERK; JNK; PI3K; AKT; MDA-7/IL-24; sorafenib; PERK; MAPK; interleukin; RCC; kidney
Categories
Funding
- PHS [P01-CA104177, R01-CA108520, R01-DK52825, R01-CA141703, R01-CA150214, R01-CA097318, R01-CA127641, R01-CA134721]
- Jim Valvano V foundation
- Department of Defense [W81XWH-10-1-0009]
- Samuel Waxman Cancer Research Foundation (SWCRF)
- National Foundation for Cancer Research (NFCR)
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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-X-L 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.
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