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

NF-κB是一种主要由p65和p50蛋白组成的转录因子，可诱导炎症细胞因子和抗凋亡蛋白。NF-κB的激活与凋亡抵抗、血管生成和癌变有关，其在细胞去分化和增殖中的基本作用。NF-κB也可能参与泌尿系统恶性肿瘤的病理生理，包括肿瘤发生、侵袭转移、化疗耐药、放射耐药、恶病质等多种机制。因此，NF-κB功能抑制剂有望成为一种抗癌药物。我们以天然产物为原料合成了一种新型强效NF-KB抑制剂——环氧喹诺霉素的去羟甲基衍生物DHMEQ。NF-κB在激素难治性前列腺癌和浸润性膀胱癌细胞中组成性活化。DHMEQ抑制NF-κB活性，诱导体内、体外激素难治性前列腺癌细胞凋亡。NF-κB的诱导活化是耐药前列腺癌细胞免受放射治疗的主要机制之一。DHMEQ预处理通过细胞周期G2/M阻滞显著增强辐照对前列腺癌细胞的抑制作用。此外，DHMEQ通过诱导细胞凋亡和抑制血管生成，显著降低膀胱癌细胞系KU-19-19的细胞活力和肿瘤生长。DHMEQ抑制MBT-2膀胱肿瘤转移模型肺转移。CPT-11联合DHMEQ对多种膀胱癌细胞系具有协同细胞毒作用。基于这些令人鼓舞的数据，DHMEQ可能对NF-κB组成性激活的激素难治性前列腺癌和浸润性膀胱癌发挥了抑制作用。血清IL-6（一种依赖NF-κB的细胞因子）水平在JCA-1荷瘤小鼠和进展性前列腺癌患者中显著升高，并产生恶病质。前列腺癌患者血清IL-6水平与血清总蛋白和白蛋白水平、血清总胆固醇水平、血红蛋白水平、体重指数、运动能力状况及生存期有显著相关性。因此，IL-6可能是前列腺癌患者恶病质复杂综合征的因素之一。在动物模型中，DHMEQ通过抑制IL-6分泌来阻止恶病质的发展。DHMEQ阻断NF-κB功能可能是一种新的、独特的分子靶向治疗侵袭性泌尿系统恶性肿瘤的抗癌策略。少

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