Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
Division of Colon and Rectal Surgery, Department of Surgery, E-Da Hospital, Kaohsiung 824, Taiwan.
Int J Mol Sci. 2018 Jun 14;19(6):1763. doi: 10.3390/ijms19061763.
Chemotherapeutic 5-fluorouracil (5-FU) combined with oxaliplatin is often used as the standard treatment for colorectal cancer (CRC). The disturbing side effects and drug resistance commonly observed in chemotherapy motivate us to develop alternative optimal therapeutic options for CRC treatment. Chrysin, a natural and biologically active flavonoid abundant in propolis, is reported to have antitumor effects on a few CRCs. However, whether and how chrysin achieves similar effectiveness to the 5-FU combination is not clear. In this study, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), western blotting, fluorescence microscopy, and reactive oxygen species (ROS) production were assayed. We found that chrysin exhibited similar inhibition of cell viability as the 5-FU combination in a panel of human CRC cells. Furthermore, the results showed that chrysin significantly increased the levels of LC3-II, an autophagy-related marker, in CRC cells, which was not observed with the 5-FU combination. More importantly, blockage of autophagy induction restored chrysin-attenuated CRC cell viability. Further mechanistic analysis revealed that chrysin, not the 5-FU combination, induced ROS generation, and in turn, inhibited the phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR). Collectively, these results imply that chrysin may be a potential replacement for the 5-FU and oxaliplatin combination to achieve antitumor activity through autophagy for CRC treatment in the future.
化疗药物 5-氟尿嘧啶（5-FU）联合奥沙利铂常用于结直肠癌（CRC）的标准治疗。化疗中常见的令人不安的副作用和耐药性促使我们开发替代的最佳治疗选择。白杨素是一种存在于蜂胶中的天然生物活性黄酮类化合物，据报道对一些 CRC 具有抗肿瘤作用。然而，白杨素是否以及如何达到与 5-FU 联合治疗相似的效果尚不清楚。在这项研究中，我们使用了 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）、western blot、荧光显微镜和活性氧（ROS）产生来进行检测。我们发现，白杨素在一系列人类 CRC 细胞中表现出与 5-FU 联合相似的抑制细胞活力的作用。此外，结果表明，白杨素显著增加了 CRC 细胞中自噬相关标志物 LC3-II 的水平，而 5-FU 联合则没有观察到这种情况。更重要的是，阻断自噬诱导恢复了白杨素减弱的 CRC 细胞活力。进一步的机制分析表明，是白杨素而不是 5-FU 联合诱导了 ROS 的产生，进而抑制了蛋白激酶 B（Akt）和雷帕霉素靶蛋白（mTOR）的磷酸化。总的来说，这些结果表明，白杨素可能是替代 5-FU 和奥沙利铂联合治疗的潜在药物，通过自噬来治疗 CRC，未来可能具有抗肿瘤活性。
