Pathophysiological role of NF k B and the efficacy of a novel NF K B inhibitor in urological cancers

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NF-κB is a transcription factor consisting mainly of p65 and p50 proteins and induces inflammatory cytokines and anti-apoptotic proteins. Activation of NF-κB is associated with apoptotic resistance, angiogenesis, and carcinogenesis by its fundamental implication in cellular dedifferentiation and proliferation. It is also possible that NF-κB is involved in the pathophysiology of urological malignancies including a variety of mechanisms of oncogenesis, invasion and metastases, chemoresistance, radioresistance, cachexia and so on. Therefore, an inhibitor of NF-κB function is expected to work as an anti-cancer agent. We have newly synthesized a dehydroxymethyl derivative of epoxyquinomicin named DHMEQ from a natural product, which is a novel and strong NF-KB inhibitor. NF-κB is constitutively activated in hormone-refractory prostate cancer and invasive bladder cancer cells. DHMEQ inhibited NF-κB activity resulting in the induction of apoptosis in hormone-refractory prostate cancer in vitro … More and in vivo. Inducible activation of NF-κB is one of the principal mechanism in which resistant prostate cancer cells are protected from radiotherapy. Pretreatment with DHMEQ significantly enhanced the inhibitory effect of irradiation through cell cycle G2/M arrest against prostate cancer cells. Furthermore, DHMEQ produced a significant decrease of cell viability and tumor growth of KU-19-19 cells, a cytokine-producing bladder cancer cell line by inducing apoptosis and inhibiting angiogenesis. DHMEQ inhibited lung metastases in metastatic model of bladder tumor using MBT-2 cells. CPT-11 in combination with DHMEQ demonstrated synergistic cytotoxic effects against several bladder cancer cell lines. Based on these encouraging data, DHMEQ possibly exerted its suppressive effect on hormone refractory prostate cancer and invasive bladder cancer in which NF-κB is constitutively activated. Serum levels of IL-6, which is an NF-κB dependent cytokine, were significantly elevated and cachexia developed in JCA-1 tumor-bearing mice as well as in prostate cancer patients with progressive disease. Serum IL-6 levels were significantly associated with serum total protein and albumin levels, serum total cholesterol levels, hemoglobin levels, body mass index, performance status and the survival in patients with prostate cancer. Therefore, IL-6 may be one of the factors contributing to the complex syndrome of cachexia in patients with prostate cancer. DHMEQ prevented the development of cachexia through the inhibition of IL-6 secretion in an animal model. Blockade of NF-κB function by DHMEQ could be a novel and unique molecular targeting anti-cancer strategy against aggressive urological malignancies. Less