Department of Pathology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 411A, Oklahoma City, OK, 73104, USA.
Department of Radiation Genetics, School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou, China.
BMC Cancer. 2018 Oct 26;18(1):1042. doi: 10.1186/s12885-018-4946-9.
Docosahexaenoic acid (DHA) is a long chain n-3 polyunsaturated fatty acid that has anticancer activity. Heme oxygenase 1 (HO-1) is a potential therapeutic target due to its cytoprotective activity in cancer cells. We recently reported that DHA induces HO-1 gene transcription in human cancer cells by augmenting the degradation of Bach1 protein, which functions as a negative regulator of HO-1. Since the degradation of Bach1 protein relies on protein phosphorylation, we hypothesized that DHA-induced HO-1 gene transcription could be attenuated by kinase inhibitors, resulting in an enhanced cytotoxicity. Sorafenib, a tyrosine kinase inhibitor, was first applied to test our hypothesis.
Human cancer cell lines and a xenograft nude mouse model were applied to test our hypothesis. Gene expression was analyzed by western blot analysis and reporter gene assay. Cell viability was analyzed using a colorimetric assay. Isobologram was applied to analyze drug action.
Pretreatment of cancer cells with Sorafenib significantly attenuated DHA-induced degradation of Bach1 protein. Consequently, DHA-induced HO-1 gene transcription was reversed by Sorafenib as evidenced by western blot and reporter gene analysis. Sorafenib acted synergistically with DHA to suppress cancer cell viability in various human cancer cell lines and suppressed tumor xenograft growth in mice fed a fish oil enriched diet (high n-3/DHA), as compared to mice fed a corn oil (high n-6) diet. Screening of the NCI-Oncology Drug Set IV identified a group of anticancer compounds, including Sorafenib, which enhanced DHA's cytotoxicity, as well as a set of compounds that attenuated DHA's cytotoxicity.
We demonstrate that sorafenib attenuates DHA-induced HO-1 expression and acts in synergy with DHA to suppress cancer cell viability and tumor growth. Considering the known health benefits of DHA and the clinical effectiveness of Sorafenib, their combination is an attractive therapeutic strategy against cancer.
二十二碳六烯酸（DHA）是一种长链 n-3 多不饱和脂肪酸，具有抗癌活性。血红素加氧酶 1（HO-1）是一种潜在的治疗靶点，因为它在癌细胞中具有细胞保护活性。我们最近报道，DHA 通过增加 Bach1 蛋白的降解来诱导人癌细胞中 HO-1 基因的转录，Bach1 蛋白作为 HO-1 的负调节剂。由于 Bach1 蛋白的降解依赖于蛋白质磷酸化，我们假设 DHA 诱导的 HO-1 基因转录可以被激酶抑制剂减弱，从而导致细胞毒性增强。索拉非尼是一种酪氨酸激酶抑制剂，首先被应用于验证我们的假设。
应用人癌细胞系和异种移植裸鼠模型来验证我们的假设。通过 Western blot 分析和报告基因分析来分析基因表达。通过比色法分析细胞活力。应用棋盘实验分析药物作用。
预先用索拉非尼处理癌细胞可显著减弱 DHA 诱导的 Bach1 蛋白降解。因此，正如 Western blot 和报告基因分析所证明的那样，索拉非尼逆转了 DHA 诱导的 HO-1 基因转录。与喂食富含鱼油（高 n-3/DHA）的玉米油（高 n-6）饮食的小鼠相比，索拉非尼与 DHA 协同作用，抑制各种人癌细胞系中的癌细胞活力，并抑制在喂食富含鱼油（高 n-3/DHA）的玉米油（高 n-6）饮食的小鼠中的肿瘤异种移植生长。对 NCI-Oncology Drug Set IV 的筛选发现了一组抗癌化合物，包括索拉非尼，它增强了 DHA 的细胞毒性，以及一组减弱 DHA 细胞毒性的化合物。
我们证明索拉非尼减弱了 DHA 诱导的 HO-1 表达，并与 DHA 协同作用抑制癌细胞活力和肿瘤生长。考虑到 DHA 的已知健康益处和索拉非尼的临床疗效，它们的组合是一种有吸引力的抗癌治疗策略。
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