Adenoviral delivery of A-FOS, an AP-1 dominant negative, selectively inhibits drug resistance in two human cancer cell lines
Adenoviral delivery of A-FOS, an AP-1 dominant negative, selectively inhibits drug resistance in two human cancer cell lines
复制标题
DOI：
10.1038/sj.cgt.7700409
复制
发表时间：
2002-01-01
影响因子：
6.4
通讯作者：
Vinson, C
中科院分区：
文献类型：
--
作者：
Bonovich, M;Olive, M;Vinson, C
激活蛋白-1（AP-1）转录因子与化疗耐药有关。为了评估AP-1抑制逆转耐药性的临床疗效，我们开发了一种表达抑制AP-1 DNA结合的显性阴性的腺病毒，命名为AdA-FOS。我们研究了AdA-FOS感染两对人类癌细胞系的后果，每对由亲本细胞和耐药衍生物组成。第一对细胞是亲本人卵巢癌细胞系A2780和顺铂抗性A2780/CP 70细胞系。第二对细胞是亲本表皮癌细胞系KB 8和多药耐药（mdr）KB 85细胞系。由于AP-1活性上调与其耐药性相关，这些细胞系被认为是AdA-FOS治疗的良好靶点。在感染药物敏感细胞和药物抗性细胞后，我们观察到在药物（通常对细胞不致命的损失）下，KB 85和A2780/CP 70细胞的细胞活力显著降低。亲本细胞系A2780和KB 8细胞不受AdA-FOS的类似影响。这种活力的降低是AdA-FOS特异性的，因为腺病毒对照（Advector）不逆转药物抗性。虽然AdA-FOS的治疗效果还需要进一步分析其他顺铂耐药细胞系和MDR细胞系，但这些结果表明AP-1是一个治疗性分子靶点，抑制AP-1 DNA结合可能在治疗化疗耐药方面具有临床价值。
Activator protein -1 (AP-1) transcription factor has been I inked to chemotherapeutic resistance. To assess the clinical efficacy of AP-1 inhibition toward reversing drug resistance, we have developed an adenovirus expressing a dominant negative that inhibits AP-1 DNA binding, named AdA-FOS. We examined the consequence of AdA-FOS infection on two paired human cancer cell lines, each pair consisting of a parental cell and the drug-resistant derivative. The first pair of cells is the parental human ovarian cancer cell line A2780 and the cisplatin-resistant A2780/CP70 cell line. The second pair of cells is the parental epidermal carcinoma cell line KB8 and the multidrug-resistant (mdr) KB85 cell line. Because of an association of up-regulated AP-1 activity with their drug resistance, these ceII lines were considered good targets of AdA- FOS therapy. Following infection of the drug-sensitive and drug-resistant cells, we observed a significant decrease in cell viability of KB85 and A2780/CP70 cells at drug (loses normally not lethal to the cell. The parental cell lines, A2780 and KB8 cells, were not similarly affected by AdA-FOS. This decrease in viability was specific to AdA-FOS as an adenovirus control (Advector) did not reverse drug resistance. Although the efficiency of AdA-FOS in therapy would need to be further analyzed with other cisplatin-resistant and mdr cell lines, these results suggest that AP-1 is a therapeutic molecular target and that inhibition of AP-1 DNA binding may be of clinical value in treating chemotherapeutic resistance.