Department of Surgery, Jikei University Hospital, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
Anticancer Res. 2012 Nov;32(11):4813-21.
Chemotherapy-induced nuclear factor kappaB (NFκB) activation is thought to play a key role in acquisition of chemoresistance by cancer cells. We focused on blockade of this activation by using the observation so-called 'desensitization' of NFκB using known NFκB activator, doxycycline.
The human pancreatic cancer cell line PANC-1 was incubated with doxycycline, followed by treatment with tumor necrosis factor (TNF)-α or paclitaxel. NFκB activity and the regulation of NFκB-related genes was analyzed.
Doxycycline induced sustained NFκB activation, followed by desensitization to further NFκB activation by TNF-α -or paclitaxel, which was accompanied by decreased expression of TNF receptor p55, p75, and epidermal growth factor receptor. Consistent with these observations, doxycycline-pre-treatment resulted in an augmentation of TNF-α- and paclitaxel-mediated cytotoxicity and apoptosis.
These data indicate the possible clinical application of desensitization of NFκB to overcome chemoresistance by conventional chemotherapy for pancreatic cancer.
化疗诱导核因子 κB（NFκB）激活被认为在癌细胞获得化疗耐药性中起关键作用。我们专注于通过使用已知的 NFκB 激活剂强力霉素来阻断这种激活，从而实现 NFκB 的所谓“脱敏”。
用人胰腺癌细胞系 PANC-1 孵育强力霉素，然后用肿瘤坏死因子（TNF）-α或紫杉醇处理。分析 NFκB 活性和 NFκB 相关基因的调节。
强力霉素诱导持续的 NFκB 激活，随后对 TNF-α或紫杉醇进一步激活 NFκB 产生脱敏作用，这伴随着 TNF 受体 p55、p75 和表皮生长因子受体表达的减少。与这些观察结果一致，强力霉素预处理导致 TNF-α 和紫杉醇介导的细胞毒性和细胞凋亡增强。
这些数据表明，通过常规化疗对胰腺癌进行 NFκB 脱敏可能具有临床应用前景。
