MacKay Medical College, Taipei, Taiwan; Department of Surgery, Division of Thoracic Surgery, MacKay Memorial Hospital, Taipei, Taiwan.
Division of Thoracic Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei City 110, Taiwan; Division of Thoracic Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan.
J Nutr Biochem. 2018 Apr;54:140-150. doi: 10.1016/j.jnutbio.2017.12.008. Epub 2017 Dec 27.
Innate or acquired drug resistance and consequent tumor relapse in lung cancer patients have been linked to activities of cancer stem cells (CSCs). Therefore, targeting CSCs is suggested as an effective approach for non-small cell lung cancer (NSCLC) therapy. In this study, we demonstrated that garcinol, a polyisoprenylated benzophenone isolated from fruiting bodies of Garcinia indica, and possessing anti-inflammatory, antioxidant, acetyltransferase inhibitory, and anticancer activities, modulates activities of lung CSCs (LCSCs) and their associated aggressiveness. Herein, we demonstrated the inhibitory effect of garcinol on the LCSC phenotype of human NSCLC cells using analytical drug cytotoxicity or cell viability, flow cytometric, and functional assay approaches. Garcinol significantly diminished the ability of the H441 and A549 NSCLC cell lines to form spheres. In parallel assays, garcinol inhibited differentiated lung cancer cell and LCSC viability in dose-dependent manners. Consistent with these observations, flow cytometric data showed that garcinol reduced the putative LCSC pool, evidenced by the dose-dependent decreasing proportion of side-population (SP) cells and associated ALDH activity in garcinol-treated H441 cells, compared to the control group. Additionally, functional assays showed that garcinol markedly diminished the ability of H441 and A549 cells to form colonies. Mechanistically, garcinol impaired phosphorylation of LRP6, a co-receptor of Wnt and STAT3. In the same assay, garcinol down-regulated β-catenin, Dvl2, Axin2, and cyclin D1 expressions in NSCLC-generated spheres, suggesting its ability to regulate the Wnt/β-catenin signaling pathway. The results were further verified in vivo using H441 LCSC mouse xenograft model where administration of garcinol significantly inhibited tumor growth. Taken together, we demonstrated herein that garcinol modulates the LCSC phenotype via regulation of Wnt/β-catenin signaling and inactivation of STAT3, thus showing that garcinol may be a putative novel anti-LCSC therapeutic agent.
天然或获得性耐药以及由此导致的肺癌患者肿瘤复发与癌症干细胞 (CSC) 的活性有关。因此，靶向 CSC 被认为是治疗非小细胞肺癌 (NSCLC) 的有效方法。在这项研究中，我们证明了 garcinol，一种从 Garcinia indica 果实中分离出来的多异戊二烯基二苯甲酮，具有抗炎、抗氧化、乙酰转移酶抑制和抗癌活性，可调节肺 CSC (LCSC) 的活性及其相关侵袭性。在这里，我们使用分析药物细胞毒性或细胞活力、流式细胞术和功能测定方法证明了 garcinol 对人 NSCLC 细胞的 LCSC 表型的抑制作用。Garcinol 显著降低了 H441 和 A549 NSCLC 细胞系形成球体的能力。在平行实验中，garcinol 以剂量依赖性方式抑制分化的肺癌细胞和 LCSC 的活力。与这些观察结果一致，流式细胞术数据表明，garcinol 降低了假定的 LCSC 池，这表现在 garcinol 处理的 H441 细胞中侧群 (SP) 细胞的比例以及相关的 ALDH 活性呈剂量依赖性降低，与对照组相比。此外，功能测定表明，garcinol 显著降低了 H441 和 A549 细胞形成集落的能力。从机制上讲，garcinol 损害了 LRP6 的磷酸化，LRP6 是 Wnt 和 STAT3 的共受体。在相同的测定中，garcinol 下调了 NSCLC 生成球体中β-catenin、Dvl2、Axin2 和 cyclin D1 的表达，表明其调节 Wnt/β-catenin 信号通路的能力。在 H441 LCSC 小鼠异种移植模型中进一步验证了这些结果，其中 garcinol 的给药显著抑制了肿瘤生长。综上所述，我们证明了 garcinol 通过调节 Wnt/β-catenin 信号和失活 STAT3 来调节 LCSC 表型，因此表明 garcinol 可能是一种潜在的新型抗 LCSC 治疗剂。
