Journal
EUROPEAN JOURNAL OF PHARMACOLOGY
Volume 919, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.ejphar.2022.174797
Keywords
Ferroptosis; Dihydroartemisinin (DHA); GPX4; Photodynamic effect (PDT); Chlorin e6 (Ce6); Lung cancer
Categories
Funding
- Hubei Provincial Natural Science Foundation [2020CFB152]
- Cultivating Project for Young Scholar at Hubei University of Medicine [2020QDJZR002, 2019QDJZR02]
- Na-tional Training Program of Innovation and Entrepreneurship for Un-dergraduates [202110929010, 202113249001]
- Innovative Research Program for Graduates of Hubei University of Medicine [YC2021016]
- Precision Medicine Project of Taihe Hospital of Shiyan [2019JJXM007]
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Photodynamic therapy (PDT) is a noninvasive, low toxicity, and photo-selective treatment method, but malignant cells may resist it. This study found that chlorin e6 (Ce6) mediated PDT showed drug resistance in lung cancer cells (LLC), which may be associated with PDT-induced DNA damage response (DDR). Dihydroartemisinin (DHA) was found to down-regulate glutathione peroxidase 4 (GPX4) and enhance the efficacy of PDT. This study provides a theoretical basis for regulating the intratumoral redox system and improving PDT efficacy against lung cancer.
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 inves-tigation 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 signif-icantly 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.
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