Han Ning, Li Liu-Gen, Peng Xing-Chun, Ma Qian-Li, Yang Zi-Yi, Wang Xi-Yong, Li Jian, Li Qi-Rui, Yu Ting-Ting, Xu Hua-Zhen, Xu Xiang, Chen Xiao, Wang Mei-Fang, Li Tong-Fei
School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Pathology, Sinopharm DongFeng General Hospital, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China.
School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China; Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei, 442000, China.
Eur J Pharmacol. 2022 Mar 15;919:174797. doi: 10.1016/j.ejphar.2022.174797. Epub 2022 Feb 3.
Photodynamic therapy (PDT) is noninvasive, low toxicity, and photo-selective, but may be resisted by malignant cells. A previous study found chlorin e6 (Ce6) mediated PDT showed drug resistance in lung cancer cells (LLC), which may be associated with PDT-induced DNA damage response (DDR). DDR may up-regulate glutathione peroxidase 4 (GPX4), which in turn degrade ROS induced by PDT. However, dihydroartemisinin (DHA) was found to down-regulate GPX4. Accordingly, the DHA was hypothesized to improve the resistance to PDT. The present work explores the mechanism of Ce6 mediated drug resistance and reveals whether DHA can enhance the efficacy of PDT by suppressing GPX4. The in vitro experiments found Ce6 treatment did not inhibit the viability of LLC within 6 h without inducing significant apoptosis, suggesting LLC were resistant to PDT. Further investigation demonstrated PDT could damage DNA and up-regulate GPX4, thus degrading the generated ROS. DHA effectively inhibited the viability of LLC and induced apoptosis. Importantly, DHA displayed a prominent inhibitory effect on the GPX4 expression and thereby triggered ferroptosis. Combining DHA with Ce6 for treatment of LLC resulted in the suppressed GPX4 and elevated ROS. Finally, the findings showed DHA combined with Ce6 exhibited superb anti-lung cancer efficacy. In summary, Ce6 PDT damages DNA, up-regulates GPX4 to degrade ROS, thereby inducing drug resistance. Down-regulation of GPX4 by DHA-triggered ferroptosis significantly enhances the efficacy of PDT. This study provides an outstanding theoretical basis for the regulation of the intratumoral redox system and improving PDT efficacy against lung cancer by herbal monomer DHA.
光动力疗法（PDT）具有非侵入性、低毒性和光选择性，但恶性细胞可能会对其产生耐药性。先前的一项研究发现，二氢卟吩e6（Ce6）介导的光动力疗法在肺癌细胞（LLC）中显示出耐药性，这可能与光动力疗法诱导的DNA损伤反应（DDR）有关。DDR可能会上调谷胱甘肽过氧化物酶4（GPX4），进而降解光动力疗法诱导产生的活性氧（ROS）。然而，已发现双氢青蒿素（DHA）可下调GPX4。因此，推测DHA可改善对光动力疗法的耐药性。本研究探讨了Ce6介导的耐药机制，并揭示了DHA是否能通过抑制GPX4来增强光动力疗法的疗效。体外实验发现，Ce6处理在6小时内未抑制LLC的活力，也未诱导明显的细胞凋亡，这表明LLC对光动力疗法具有耐药性。进一步研究表明，光动力疗法可损伤DNA并上调GPX4，从而降解产生的ROS。DHA有效抑制了LLC的活力并诱导细胞凋亡。重要的是，DHA对GPX4的表达具有显著的抑制作用，从而引发铁死亡。将DHA与Ce6联合用于LLC的治疗可抑制GPX4并提高ROS水平。最后，研究结果表明，DHA与Ce6联合使用具有出色的抗肺癌疗效。总之，Ce6光动力疗法损伤DNA，上调GPX4以降解ROS，从而诱导耐药性。DHA引发的铁死亡导致GPX4下调，显著增强了光动力疗法的疗效。本研究为调节肿瘤内氧化还原系统以及通过草药单体DHA提高光动力疗法对肺癌的疗效提供了出色的理论依据。
