Hecht Markus, Harrer Thomas, Körber Verena, Sarpong Eric O, Moser Fabian, Fiebig Nora, Schwegler Manuela, Stürzl Michael, Fietkau Rainer, Distel Luitpold V
Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Department of Internal Medicine 3 (Infectious Diseases Section), Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, D-91054 Erlangen, Germany.
Oncol Lett. 2018 Feb;15(2):1728-1736. doi: 10.3892/ol.2017.7523. Epub 2017 Dec 5.
The non-nucleoside reverse transcriptase inhibitor (NNRTI) Efavirenz is frequently used in human immunodeficiency virus treatment, but also efficient against cancer in mouse models. Its radiosensitizing effect makes it a promising drug for combination with radiotherapy. The efficacy of Efavirenz combined with irradiation was assessed with immunostaining of DNA-damage markers and colony formation assays in BxPC-3 pancreatic cancer cells. Gene expression and protein phosphorylation of the Efavirenz-sensitive BxPC-3 cells was compared to the resistant primary fibroblasts SBL-5. Oxidative stress, mitochondrial damage and cell death were studied with live-cell microscopy and flow cytometry. Combined Efavirenz and radiation significantly increased the number of γH2AX and phospho-ataxia telangiectasia mutated foci. Efavirenz and ionizing radiation had a synergistic effect using the clonogenic survival assay. Efavirenz selectively induced cell death in the BxPC-3 cells. The differing gene expression of cell cycle and apoptotic regulator genes in both cell cultures after Efavirenz treatment match with this selective effect against cancer cells. In the phosphoprotein array, an early phosphorylation of extracellular signal-related kinase 1/2 and p38 mitogen-activated protein kinase was notably detected in the cancer cells. The phosphorylation of AKT decreased in the cancer cells whereas it increased in the fibroblasts. Oxidative stress and mitochondrial membrane depolarization appeared in the cancer cells immediately after Efavirenz treatment, but not in the fibroblasts. Efavirenz has an anti-cancer effect against pancreatic cancer mainly by the induction of oxidative stress. The antitumor potential of Efavirenz and radiotherapy are additive.
非核苷类逆转录酶抑制剂（NNRTI）依非韦伦常用于人类免疫缺陷病毒治疗，但在小鼠模型中对癌症也有效。其放射增敏作用使其成为一种有前景的与放疗联合使用的药物。通过对BxPC-3胰腺癌细胞进行DNA损伤标志物免疫染色和集落形成试验，评估了依非韦伦与照射联合的疗效。将对依非韦伦敏感的BxPC-3细胞的基因表达和蛋白质磷酸化与耐药的原代成纤维细胞SBL-5进行了比较。通过活细胞显微镜和流式细胞术研究了氧化应激、线粒体损伤和细胞死亡情况。依非韦伦与辐射联合显著增加了γH2AX和磷酸化共济失调毛细血管扩张突变灶的数量。使用克隆形成存活试验，依非韦伦和电离辐射具有协同作用。依非韦伦选择性诱导BxPC-3细胞死亡。依非韦伦处理后，两种细胞培养物中细胞周期和凋亡调节基因的不同基因表达与这种对癌细胞的选择性作用相匹配。在磷酸蛋白阵列中，在癌细胞中显著检测到细胞外信号调节激酶1/2和p38丝裂原活化蛋白激酶的早期磷酸化。癌细胞中AKT的磷酸化降低，而成纤维细胞中则升高。依非韦伦处理后，癌细胞立即出现氧化应激和线粒体膜去极化，但成纤维细胞中未出现。依非韦伦主要通过诱导氧化应激对胰腺癌具有抗癌作用。依非韦伦和放疗的抗肿瘤潜力具有相加性。
