Establishment of gene therapy targeting bcl-2 and NF κB for urological malignancies

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NF-kappa B activity was increased in 15 out of 45 renal cell carcinoma and correlated with serum CRP elevation. Forced expression of antisense cDNA of IkappaBalpha, in TRAIL-sensitive cell lines with a low NF-kappaB activity resulted in constitutive activation of NF-kappaB and resistance to TRAIL-induced apoptosis. Adenoviral expression of a stable form of IkappaBalpha in the TRAIL-resistant cell lines induced apoptosis. An NF-kappaB function inhibitor, DHMEQ, has recently been designed and synthesized. NF-kappaB activation was shown to maintain the viability of bladder cancer cells (KU-19-19) and DHMEQ inhibited constitutively activated NF-kappaB and consequently apoptosis was induced. DHMEQ also induced apoptosis through the inhibition of NFkappaB activity in hormone refractory prostate cancer. Antisense bcl-2 oligodeoxynucleotides significantly decreased the viability of an androgen-independent subline (SCAT cells) derived from mouse androgen-dependent mammary carcinoma cells. Direct sequence analysis showed no mutations in the AR of either androgen-dependent or -independent cells. Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity in hormone independent prostate cancer cells (PC3). Our data suggest that a molecular approach targeting bcl-2 appears to be a promising therapy in hormone independent prostate cancer. Locally advanced RCC cases had a significantly higher rate of increased C/EBP-beta activity determined by EMSA, suggesting that the increased activation of C/EBP-beta may contribute to promote tumor invasiveness and render a malignant phenotype of RCC. Our study also identified STAT3 to be a major mediator of IL-6-induced proliferation of renal cancer cells. Because the Jak specific inhibitor AG 490 effectively inhibited the IL-6-induced STAT3 activity and induced apoptosis, the blockade of the STAT3 signaling pathways is considered to be potentially useful as a novel therapeutic approach for RCC.