Department of Health and Nutritional Sciences, South Dakota State University, Box 2275A, Brookings, SD 57007, USA.
Int J Mol Sci. 2019 Feb 27;20(5):1027. doi: 10.3390/ijms20051027.
Aldehyde dehydrogenase 1 (ALDH1) is a cytosolic marker of cancer stem cells (CSCs), which are a sub-population within heterogeneous tumor cells. CSCs associate with therapy-resistance, self-renewal, malignancy, tumor-relapse, and reduced patient-survival window. ALDH1-mediated aldehyde scavenging helps CSCs to survive a higher level of oxidative stress than regular cancer cells. Cruciferous vegetable-derived phenethyl isothiocyanate (PEITC) selectively induces reactive oxygen species (ROS), leading to apoptosis of cancer cells, but not healthy cells. However, this pro-oxidant role of PEITC in CSCs is poorly understood and is investigated here. In a HeLa CSCs model (hCSCs), the sphere-culture and tumorsphere assay showed significantly enriched ALDH CSCs from HeLa parental cells ( < 0.05). Aldefluor assay and cell proliferation assay revealed that PEITC treatments resulted in a reduced number of ALDH hCSCs in a concentration-dependent manner ( < 0.05). In the ROS assay, PEITC promoted oxidative stress in hCSCs ( ≤ 0.001). Using immunoblotting and flow cytometry techniques, we reported that PEITC suppressed the cancer-associated transcription factor (Sp1) and a downstream multidrug resistance protein (P-glycoprotein) (both, < 0.05). Furthermore, PEITC-treatment of hCSCs, prior to xenotransplantation in mice, lowered the in vivo tumor-initiating potential of hCSCs. In summary, PEITC treatment suppressed the proliferation of ALDH1 expressing cancer stem cells as well as key factors that are involved with drug-resistance, while promoting oxidative stress and apoptosis in hCSCs.
醛脱氢酶 1（ALDH1）是癌症干细胞（CSC）的细胞质标志物，CSC 是异质肿瘤细胞中的一个亚群。CSC 与治疗耐药性、自我更新、恶性肿瘤、肿瘤复发和患者生存窗口缩小有关。ALDH1 介导的醛清除有助于 CSCs 在比普通癌细胞更高水平的氧化应激下存活。十字花科蔬菜衍生的苯乙基异硫氰酸酯（PEITC）选择性地诱导活性氧（ROS），导致癌细胞凋亡，但对健康细胞没有影响。然而，PEITC 在 CSCs 中的这种促氧化作用知之甚少，本研究对此进行了探讨。在 HeLa CSCs 模型（hCSCs）中，球体培养和肿瘤球体测定显示，从 HeLa 亲本细胞中明显富集了 ALDH CSCs（<0.05）。Aldefluor 测定和细胞增殖测定显示，PEITC 处理以浓度依赖的方式导致 ALDH hCSCs 的数量减少（<0.05）。在 ROS 测定中，PEITC 促进了 hCSCs 中的氧化应激（≤0.001）。通过免疫印迹和流式细胞术技术，我们报告称，PEITC 抑制了癌症相关转录因子（Sp1）和下游多药耐药蛋白（P-糖蛋白）（均<0.05）。此外，在将 hCSCs 异种移植到小鼠之前，用 PEITC 处理 hCSCs 降低了 hCSCs 的体内肿瘤起始潜能。总之，PEITC 处理抑制了 ALDH1 表达的癌症干细胞的增殖以及与耐药性相关的关键因素，同时促进了 hCSCs 中的氧化应激和细胞凋亡。
