Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 130-701, Republic of Korea.
Carcinogenesis. 2012 Dec;33(12):2488-98. doi: 10.1093/carcin/bgs302. Epub 2012 Oct 1.
Paclitaxel (Taxol) is currently used as the front-line chemotherapeutic agent for several cancers including ovarian carcinoma; however, the drug frequently induces drug resistance through multiple mechanisms. The new strategy of using natural compounds in combination therapies is highly attractive because those compounds may enhance the efficacy of chemotherapy. In this study, we found that tectorigenin, an isoflavonoid isolated from flower of Pueraria thunbergiana, enhanced the growth-inhibitory effect of paclitaxel in paclitaxel-resistant ovarian cancer cells (MPSC1(TR), A2780(TR) and SKOV3(TR)) as well as their naive counterparts. The combination of tectorigenin with paclitaxel resulted in a synergistic apoptosis compared with either agent alone through activation of caspases-3, -8 and -9. Treatment with tectorigenin inhibited the nuclear translocation of NFκB and the expression of NFκB-dependent genes such as FLIP, XIAP, Bcl-2, Bcl-xL and COX-2, which are known to be associated with chemoresistance. In addition, the tectorigenin-paclitaxel combination inhibited the phosphorylation of IκB and IKK and the activation of Akt in paclitaxel-resistant cancer cells. Moreover, tectorigenin-paclitaxel-induced cell growth inhibition was enhanced by pretreatment with the Akt inhibitor LY294002 or overexpression of the dominant negative Akt (Akt-DN), but reduced by overexpression of constitutively activated Akt (Akt-Myr). Furthermore, we found that Akt-Myr, at least in part, reversed tectorigenin-paclitaxel-induced nuclear translocation of NFκB and the phosphorylation of IκB and IKK. These data suggest that tectorigenin could sensitize paclitaxel-resistant human ovarian cancer cells through inactivation of the Akt/IKK/IκB/NFκB signaling pathway, and promise a new intervention to chemosensitize paclitaxel-induced cytotoxicity in ovarian cancer.
紫杉醇（Taxol）目前被用作包括卵巢癌在内的几种癌症的一线化疗药物；然而，该药物常通过多种机制诱导耐药性。使用天然化合物联合治疗的新策略非常有吸引力，因为这些化合物可能增强化疗的疗效。在这项研究中，我们发现从葛花中分离得到的异黄酮化合物葛根素增强了紫杉醇耐药卵巢癌细胞（MPSC1(TR)、A2780(TR)和 SKOV3(TR)）及其相应的敏感细胞对紫杉醇的生长抑制作用。葛根素与紫杉醇联合使用通过激活 caspase-3、-8 和 -9，导致与单独使用任一药物相比，协同诱导细胞凋亡。葛根素处理抑制了 NFκB 的核易位和 NFκB 依赖性基因（如 FLIP、XIAP、Bcl-2、Bcl-xL 和 COX-2）的表达，这些基因与化疗耐药性有关。此外，葛根素-紫杉醇联合抑制了紫杉醇耐药癌细胞中 IκB 和 IKK 的磷酸化以及 Akt 的激活。此外，用 Akt 抑制剂 LY294002 预处理或过表达显性失活 Akt（Akt-DN）增强了葛根素-紫杉醇诱导的细胞生长抑制，但过表达组成型激活 Akt（Akt-Myr）则减弱了这种抑制作用。此外，我们发现 Akt-Myr 至少部分逆转了葛根素-紫杉醇诱导的 NFκB 核易位以及 IκB 和 IKK 的磷酸化。这些数据表明，葛根素可以通过失活 Akt/IKK/IκB/NFκB 信号通路使紫杉醇耐药的人卵巢癌细胞敏感化，并有望为化疗增敏紫杉醇诱导的卵巢癌细胞毒性提供新的干预措施。
