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

核因子-κB是一种主要由p65和p50蛋白组成的转录因子，可诱导炎性细胞因子和抗凋亡蛋白。NF-κB的激活与细胞的抗凋亡、血管生成和肿瘤的发生有关，因为它在细胞去分化和增殖中具有重要意义。NF-κB也可能参与了泌尿系统恶性肿瘤的病理生理过程，包括肿瘤发生、侵袭转移、化疗耐药、辐射耐药、恶病质等多种机制。因此，核因子-κB功能的抑制剂有望作为抗癌剂发挥作用。我们从天然产物中新合成了环氧喹诺米星的脱羟甲基衍生物DHMEQ，它是一种新型的、强大的核因子-KB抑制剂。在激素不敏感的前列腺癌和浸润性膀胱癌细胞中，NF-κB被结构性激活。DHMEQ抑制NF-κB活性诱导激素非依赖性前列腺癌…细胞凋亡更多的是在体内。NF-κB的可诱导激活是耐药前列腺癌抵抗放射治疗的主要机制之一。DHMEQ可通过细胞周期G2/M期阻滞显著增强照射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，显著降低了膀胱癌细胞系KU-19-19的细胞活力和肿瘤生长。DHMEQ通过MBT-2细胞抑制膀胱癌转移模型的肺转移。CPT-11与DHMEQ联合应用对多种膀胱癌细胞株具有协同杀伤作用。基于这些令人鼓舞的数据，DHMEQ可能对激素难治性前列腺癌和NF-κB结构性激活的浸润性膀胱癌发挥抑制作用。IL-6是一种依赖于核因子-κB的细胞因子，在荷瘤小鼠和进展期前列腺癌患者中，血清IL-6水平显著升高并出现恶病质。血清IL-6水平与前列腺癌患者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、运动状态和生存时间显著相关。因此，IL-6可能是前列腺癌患者恶病质复杂综合征的致病因素之一。在动物模型中，DHMEQ通过抑制IL-6的分泌来预防恶病质的发展。DHMEQ阻断NF-κB功能可能是一种新颖而独特的分子靶向抗癌策略，可用于治疗侵袭性泌尿系统恶性肿瘤。较少

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