Combined treatment with TNF-α/gefitinib alleviates the resistance to gefitinib in PC-9 cells
Combined treatment with TNF-α/gefitinib alleviates the resistance to gefitinib in PC-9 cells
复制标题
DOI：
10.1097/cad.0b013e32832f4b64
复制
发表时间：
2009-10-01
影响因子：
2.3
通讯作者：
Lu, Yan-Jun
中科院分区：
文献类型：
--
作者：
Ji, Yuan;Ma, Sheng-lin;Lu, Yan-Jun
吉非替尼已被批准用于治疗非小细胞肺癌患者。然而，其效率受到耐药性发展的限制。迫切需要用吉非替尼治疗复发的非小细胞肺癌病例的额外治疗。为了探讨Gefitinib获得性耐药的机制，我们建立了长期接触Gefitinib后耐药的人肺癌细胞系PC-9-ZD。PC-9-ZD细胞对吉非替尼的耐药性高于其亲本PC-9细胞。我们发现，吉非替尼降低了p-Akt水平，伴随着p21水平的升高，抑制了cdk2/4和cyClinE/d1的活性，从而导致细胞周期进程受阻，仅在亲代PC-9细胞中通过G(1)期停滞，从而抑制了细胞生长。我们目前的数据表明，在长期暴露于吉非替尼后，p-Akt水平升高和p21水平降低的PC-9-ZD细胞的存活抵抗了吉非替尼对细胞生长的进一步抑制。为了探索提高Gefitinib疗效的新策略，我们用肿瘤坏死因子-α(TNF-α)处理PC-9-ZD细胞，发现对Gefitinib具有获得性耐药的细胞对TNF-α的敏感性增加，这与PC-9-ZD细胞中核因子(NF)kappa B/p65的低激活水平有关。肿瘤坏死因子-α诱导PC-9-ZD细胞活化的核因子kappaB/p65升高，同时诱导p21水平升高，从而导致PC-9-ZD细胞对吉非替尼的敏感性增加。与我们先前观察到的p21是以一种依赖于核因子kappaB/p65的方式被诱导相一致，我们得出结论，p21在介导吉非替尼抑制细胞生长的过程中起着重要作用。因此，我们提出联合应用肿瘤坏死因子-α/吉非替尼是治疗对吉非替尼产生耐药性的肿瘤的有效治疗策略。抗癌药物20：832-837(C)2009沃尔特斯·克鲁沃健康垂直酒吧Lippincott Williams&Wilkins。
Gefitinib has been approved for the treatment of patients with non-small cell lung cancer. However, its efficiency is limited by the development of drug resistance. Additional treatments for cases of non-small cell lung cancer relapsing with treatment with gefitinib are urgently required. To investigate the mechanisms of acquired resistance to gefitinib, we established PC-9-ZD, a human lung cancer cell line resistant to gefitinib after long-term exposure to the drug. PC-9-ZD cells showed more resistance to gefitinib than their parental PC-9 cells. We show that gefitinib reduces p-Akt levels, concomitant with elevation of p21 levels and suppression of cdk2/4 and cyclinE/D1 activities, which result in impaired cell cycle progression through G(1) arrest only in parental PC-9 cells, in which it inhibits growth. Our present data suggested that after long-term exposure to gefitinib, the survival of PC-9-ZD cells with heightened levels of p-Akt and reduced levels of p21 resisted further gefitinib-induced inhibition of cell growth. To explore a new strategy to improve the efficacy of gefitinib, we treated the cells with tumor necrosis factor-alpha (TNF-alpha) and found that the cells with acquired resistance to gefitinib showed increasing sensitivity to TNF-alpha, which correlated with the low activation level of nuclear factor (NF)kappa B/p65 in PC-9-ZD cells. TNF-alpha treatment induced an elevated activated NF kappa B/p65, concomitant with induced p21 levels, which resulted in increased sensitivity to gefitinib in PC-9-ZD cells. Consistent with our earlier observation that p21 is induced in an NF kappa B/p65-dependent manner, we conclude that p21 plays an important role in mediating cell growth inhibition by gefitinib. Thus, we proposed that combined treatment with TNF-alpha/gefitinib is an efficient therapeutic strategy for tumors that develop resistance to gefitinib. Anti-Cancer Drugs 20:832-837 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.