Basic research in molecular targeting therapy of malignant gliomas against NF-kB

已有报道称，核因子-kB(nudear factor-kB)是一种转录因子，控制多种肿瘤细胞的增殖。这种非活性形式的因子被转移到细胞质中，一旦被放射或化疗药物激活，核转录因子-kB就被转移到细胞核中，以防止细胞凋亡。作者先前报道，在恶性胶质瘤细胞中，核因子-kB被结构性激活，抑制核因子-kB导致培养的人脑胶质瘤细胞的生长受到抑制。因此，作者认为核因子-kB是恶性胶质瘤治疗策略的潜在分子靶点。本研究利用人脑胶质瘤标本，研究了活化的核因子-kB的免疫组织化学发现与Mib-1染色指数的关系。另外，采用四甲基偶氮唑盐比色法分析了抗核因子-kB药物匹伐他汀对恶性胶质瘤细胞株A172辐射敏感性的影响。通过核…证实了活化形式的核因子-kB的存在在所有胶质瘤标本中有更多的定位。正常脑组织中未见活化形式的核因子-kB。活化形式的核因子-kB染色强度与Mib-1染色指数相关。这一发现表明，胶质瘤中NF-kB的结构性激活与生长潜能有关。抗核因子-kB(Pitavastatin，Pitavastatin)对培养的人脑胶质瘤细胞株(A172)辐射敏感性的增强作用。在单层培养中，Pitavastatin(100μM)对A172细胞的辐射敏感性无明显抑制作用，但提高了A172细胞的辐射敏感性。致敏增敏倍数为5。用培养的A172细胞富核裂解液对活化形式的核因子-kB(P50)进行免疫印迹。15Gy射线照射后，对照组A172细胞中活化形式的核因子-kB(P50)迅速增加。而A172细胞经100μM处理后，核因子-kB的活化形式不增加(P50)。这一发现可能在抗NF-kB药物Pitavastin对胶质瘤细胞的放射增敏机制中具有重要意义。综上所述，我们的研究表明，在所有胶质瘤细胞中都有NF-kB的结构性激活。抑制N-kB既能有效抑制胶质瘤生长，又能增强胶质瘤细胞的辐射增敏作用。因此，核因子-kB是建立恶性胶质瘤治疗新策略的潜在分子靶点。较少

It has been reported that NF-kB (nudear factor-kB) is a transcription factor, which controls cell proliferation of many kinds of cancer cells. This factor in inactive form is translocated in the cytoplasm and once activated by radiation or chemotherapeutic agent, NF-kB translocates into nucleus to prevent apoptosis. The authors previously reported that NF-kB is constitutively activated in malignant glioma cells, and inhibition of NF-kB resulted in the growth inhibition of the cultured human glioma cells. Therefore, the authors assume that NF-kB is the potential molecular target in the treatment strategy of malignant gliomas.This study investigated the relationship between the immunohistochemical finding of activated NF-kB and Mib-1 staining index using human glioma specimin. In addition, change of the radiation sensitivity of malignant glioma cell line (A172) by anti-NF-kB drug (pitavastatin) was analysed using MTT assay. The presence of activated form of NF-kB was confirmed by nuclear … More localization in all glioma specimin. Normal brain tissue was negative for activated form of NF-kB. Intensity of the activated form of NF-kB staining was correlated with Mib-1 staining index. This finding suggested that constitutive activation of NF-kB in gliomas were associated with growth potential. Radiation sensitivity of cultured glioma cell line (A172) was enhanced by anti-NF-kB (pitavastatin) pretreatment Pitavastatin at the concentration of 100μM was not inhibitory to A172 cells in monolayer culture, but it enhanced radiation sensitivity of A172 cells by MTT assay. Sensitization enhancement ratio was 5. Immunoblotting of the activated form of NF-kB (p50) was performed using nuclear rich lysate of cultured A172 cells. Activated form of NF-kB (p50) rapid ly increased in control A172 cells ater exposure to 15Gy radiation. However, pretreatment of A172 cells at the concentration of 100μM resulted in no increase of the activated form of NF-kB (p50). This finding may be important in the mechanism of radiosensitization of glioma cells by anti-NF-kB drug pitavastatin.In conclusion, our study demonstrate that NF-kB is constitutively activated in all of the glioma cells. Inhibition of N-kB is effective both inhibiting glioma growth and rasiosensitization of glioma cells. Therefore, NF-kB is potential molecular target to establish the new treatment strategy for malignant gliomas. Less