Faculty of Medicine, University of Belgrade, Doktora Subotića 8, Belgrade, Serbia.
PLoS One. 2013;8(1):e54044. doi: 10.1371/journal.pone.0054044. Epub 2013 Jan 11.
Achieving an effective treatment of cancer is difficult, particularly when resistance to conventional chemotherapy is developed. P-glycoprotein (P-gp) activity governs multi-drug resistance (MDR) development in different cancer cell types. Identification of anti-cancer agents with the potential to kill cancer cells and at the same time inhibit MDR is important to intensify the search for novel therapeutic approaches. We examined the effects of sulfinosine (SF), a quite unexplored purine nucleoside analog, in MDR (P-gp over-expressing) non-small cell lung carcinoma (NSCLC) and glioblastoma cell lines (NCI-H460/R and U87-TxR, respectively). SF showed the same efficacy against MDR cancer cell lines and their sensitive counterparts. However, it was non-toxic for normal human keratinocytes (HaCaT). SF induced caspase-dependent apoptotic cell death and autophagy in MDR cancer cells. After SF application, reactive oxygen species (ROS) were generated and glutathione (GSH) concentration was decreased. The expression of key enzyme for GSH synthesis, gamma Glutamyl-cysteine-synthetase (γGCS) was decreased as well as the expression of gst-π mRNA. Consequently, SF significantly decreased the expression of hif-1α, mdr1 and vegf mRNAs even in hypoxic conditions. SF caused the inhibition of P-gp (coded by mdr1) expression and activity. The accumulation of standard chemotherapeutic agent--doxorubicin (DOX) was induced by SF in concentration- and time-dependent manner. The best effect of SF was obtained after 72 h when it attained the effect of known P-gp inhibitors (Dex-verapamil and tariquidar). Accordingly, SF sensitized the resistant cancer cells to DOX in subsequent treatment. Furthermore, SF decreased the experssion of vascular endothelial growth factor (VEGF) on mRNA and protein level and modulated its secretion. In conclusion, the effects on P-gp (implicated in pharmacokinetics and MDR), GSH (implicated in detoxification) and VEGF (implicated in tumor-angiogenesis and progression) qualify SF as multi-potent anti-cancer agent, which use must be considered, in particular for resistant malignancies.
实现癌症的有效治疗很困难，尤其是当对常规化疗产生耐药性时。P-糖蛋白（P-gp）的活性控制着不同癌细胞类型的多药耐药（MDR）的发展。鉴定具有杀死癌细胞同时抑制 MDR 潜力的抗癌药物对于加强寻找新的治疗方法非常重要。我们研究了磺酰肌氨酸（SF）在多药耐药（P-gp 过表达）非小细胞肺癌（NSCLC）和神经胶质瘤细胞系（NCI-H460/R 和 U87-TxR）中的作用。SF 对 MDR 癌细胞系及其敏感对应物具有相同的疗效。然而，它对正常人角质形成细胞（HaCaT）没有毒性。SF 在 MDR 癌细胞中诱导 caspase 依赖性细胞凋亡和自噬。SF 应用后，产生活性氧（ROS）并降低谷胱甘肽（GSH）浓度。GSH 合成的关键酶γ谷氨酰半胱氨酸合成酶（γGCS）的表达以及 gst-π mRNA 的表达均降低。结果，SF 甚至在缺氧条件下显著降低 hif-1α、mdr1 和 vegf mRNA 的表达。SF 抑制 P-gp（由 mdr1 编码）的表达和活性。SF 以浓度和时间依赖性方式诱导标准化疗药物阿霉素（DOX）的积累。当 SF 在 72 小时时获得已知 P-gp 抑制剂（地塞米松-维拉帕米和塔里奎达）的效果时，SF 达到最佳效果。因此，SF 在后续治疗中使耐药癌细胞对 DOX 敏感。此外，SF 在 mRNA 和蛋白水平上降低了血管内皮生长因子（VEGF）的表达并调节其分泌。总之，SF 对 P-gp（涉及药代动力学和 MDR）、GSH（涉及解毒）和 VEGF（涉及肿瘤血管生成和进展）的作用使其成为一种多效抗癌药物，应考虑使用，特别是对于耐药性恶性肿瘤。
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