Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategy
Objective: Photodynamic therapy (PDT) primarily treats skin diseases or cancer by generating reactive oxygen species (ROS) to damage cellular DNA, yet drug resistance limits its application. To tackle this problem, the present study was carried out to improve the efficacy of chlorin e6 (Ce6)-PDT usi...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-02-01
|
| Series: | Photodiagnosis and Photodynamic Therapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1572100023006440 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850062229475426304 |
|---|---|
| author | Zi-Yi Yang Liu-Gen Li Yi-Lian Xiong Nan-Nan Chen Ting-Ting Yu Hai-Tao Li Tao Ren Hui You Xiao Wang Tong-Fei Li Mei-Fang Wang Jun Hu |
| author_facet | Zi-Yi Yang Liu-Gen Li Yi-Lian Xiong Nan-Nan Chen Ting-Ting Yu Hai-Tao Li Tao Ren Hui You Xiao Wang Tong-Fei Li Mei-Fang Wang Jun Hu |
| author_sort | Zi-Yi Yang |
| collection | DOAJ |
| description | Objective: Photodynamic therapy (PDT) primarily treats skin diseases or cancer by generating reactive oxygen species (ROS) to damage cellular DNA, yet drug resistance limits its application. To tackle this problem, the present study was carried out to improve the efficacy of chlorin e6 (Ce6)-PDT using Cepharanthine (CEP) as well as to reveal the potential molecular mechanism. Materials and methods: Lewis lung cancer cell line (LLC) was utilized as the cancer cell model. chlorin e6 (Ce6) acted as the photosensitizer to induce PDT. The in vitro anti-cancer efficacy was measured by CCK-8, Annexin-V/PI staining, and migration assay. The Ce6 uptake was observed using flow cytometry and confocal microscopy. The ROS generation was detected by the DCFH-DA probe. The analysis of MutT Homolog 1 (MTH1) expression, correlation, and prognosis in databases was conducted by bioinformatic. The MTH1 expression was detected through western blots (WB). DNA damage was assayed by WB, immunofluorescent staining, and comet assay. Results: Ce6-PDT showed robust resistance in lung cancer cells under certain conditions, as evidenced by the unchanged cell viability and apoptosis. The subsequent findings confirmed that the uptake of Ce6 and MTH1 expression was enhanced, but ROS generation with laser irradiation was not increased in LLC, which indicated that the ROS scavenge may be the critical reason for resistance. Surprisingly, bioinformatic and in vitro experiments identified that MTH1, which could prevent the DNA from damage of ROS, was highly expressed in lung cancer and thereby led to the poor prognosis and could be further up-regulated by Ce6 PDT. CEP exhibited a dose-dependent suppressive effect on the lung cancer cells. Further investigations presented that CEP treatment boosted ROS production, thereby resulting in DNA double-strand breakage (DDSB) with activation of MTH1, indicating that CEP facilitated Ce6-PDT-mediated DNA damage. Finally, the combination of CEP and Ce6-PDT exhibited prominent ROS accumulation, MTH1 inhibition, and anti-lung cancer efficacy, which had synergistic pro-DNA damage properties. Conclusion: Collectively, highly expressed MTH1 and the failure of ROS generation lead to PDT resistance in lung cancer cells. CEP facilitates ROS generation of PDT, thereby promoting vigorous DNA damage, inactivating MTH1, alleviating PDT resistance, and ameliorating the anti-cancer efficacy of Ce6-PDT, provides a novel approach for augmented PDT. |
| format | Article |
| id | doaj-art-beef84f2f2ac4ba882b9b0ce8746675b |
| institution | DOAJ |
| issn | 1572-1000 |
| language | English |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Photodiagnosis and Photodynamic Therapy |
| spelling | doaj-art-beef84f2f2ac4ba882b9b0ce8746675b2025-08-20T02:49:59ZengElsevierPhotodiagnosis and Photodynamic Therapy1572-10002024-02-014510391710.1016/j.pdpdt.2023.103917Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategyZi-Yi Yang0Liu-Gen Li1Yi-Lian Xiong2Nan-Nan Chen3Ting-Ting Yu4Hai-Tao Li5Tao Ren6Hui You7Xiao Wang8Tong-Fei Li9Mei-Fang Wang10Jun Hu11Hubei Key Laboratory of Embryonic Stem Cell Research, 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, ChinaHubei Key Laboratory of Embryonic Stem Cell Research, 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, ChinaHubei Key Laboratory of Embryonic Stem Cell Research, 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, ChinaHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, ChinaHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, China; Department of Pathology, Renmin Hospital of Shiyan, Hubei University of Medicine, Shiyan, Hubei 442000, ChinaDepartment of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, ChinaDepartment of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, ChinaDepartment of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, ChinaDepartment of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, ChinaHubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, China; Corresponding authors.Department of Respiratory, Taihe Hospital of Shiyan, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, China; Corresponding authors.Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Hubei University of Medicine, Renmin road No. 30, Shiyan, Hubei 442000, China; Corresponding authors.Objective: Photodynamic therapy (PDT) primarily treats skin diseases or cancer by generating reactive oxygen species (ROS) to damage cellular DNA, yet drug resistance limits its application. To tackle this problem, the present study was carried out to improve the efficacy of chlorin e6 (Ce6)-PDT using Cepharanthine (CEP) as well as to reveal the potential molecular mechanism. Materials and methods: Lewis lung cancer cell line (LLC) was utilized as the cancer cell model. chlorin e6 (Ce6) acted as the photosensitizer to induce PDT. The in vitro anti-cancer efficacy was measured by CCK-8, Annexin-V/PI staining, and migration assay. The Ce6 uptake was observed using flow cytometry and confocal microscopy. The ROS generation was detected by the DCFH-DA probe. The analysis of MutT Homolog 1 (MTH1) expression, correlation, and prognosis in databases was conducted by bioinformatic. The MTH1 expression was detected through western blots (WB). DNA damage was assayed by WB, immunofluorescent staining, and comet assay. Results: Ce6-PDT showed robust resistance in lung cancer cells under certain conditions, as evidenced by the unchanged cell viability and apoptosis. The subsequent findings confirmed that the uptake of Ce6 and MTH1 expression was enhanced, but ROS generation with laser irradiation was not increased in LLC, which indicated that the ROS scavenge may be the critical reason for resistance. Surprisingly, bioinformatic and in vitro experiments identified that MTH1, which could prevent the DNA from damage of ROS, was highly expressed in lung cancer and thereby led to the poor prognosis and could be further up-regulated by Ce6 PDT. CEP exhibited a dose-dependent suppressive effect on the lung cancer cells. Further investigations presented that CEP treatment boosted ROS production, thereby resulting in DNA double-strand breakage (DDSB) with activation of MTH1, indicating that CEP facilitated Ce6-PDT-mediated DNA damage. Finally, the combination of CEP and Ce6-PDT exhibited prominent ROS accumulation, MTH1 inhibition, and anti-lung cancer efficacy, which had synergistic pro-DNA damage properties. Conclusion: Collectively, highly expressed MTH1 and the failure of ROS generation lead to PDT resistance in lung cancer cells. CEP facilitates ROS generation of PDT, thereby promoting vigorous DNA damage, inactivating MTH1, alleviating PDT resistance, and ameliorating the anti-cancer efficacy of Ce6-PDT, provides a novel approach for augmented PDT.http://www.sciencedirect.com/science/article/pii/S1572100023006440Photodynamic therapy (PDT)Cepharanthine (CEP)MTH1Drug resistanceDNA damageLung cancer |
| spellingShingle | Zi-Yi Yang Liu-Gen Li Yi-Lian Xiong Nan-Nan Chen Ting-Ting Yu Hai-Tao Li Tao Ren Hui You Xiao Wang Tong-Fei Li Mei-Fang Wang Jun Hu Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategy Photodiagnosis and Photodynamic Therapy Photodynamic therapy (PDT) Cepharanthine (CEP) MTH1 Drug resistance DNA damage Lung cancer |
| title | Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategy |
| title_full | Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategy |
| title_fullStr | Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategy |
| title_full_unstemmed | Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategy |
| title_short | Cepharanthine synergizes with photodynamic therapy for boosting ROS-driven DNA damage and suppressing MTH1 as a potential anti-cancer strategy |
| title_sort | cepharanthine synergizes with photodynamic therapy for boosting ros driven dna damage and suppressing mth1 as a potential anti cancer strategy |
| topic | Photodynamic therapy (PDT) Cepharanthine (CEP) MTH1 Drug resistance DNA damage Lung cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1572100023006440 |
| work_keys_str_mv | AT ziyiyang cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT liugenli cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT yilianxiong cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT nannanchen cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT tingtingyu cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT haitaoli cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT taoren cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT huiyou cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT xiaowang cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT tongfeili cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT meifangwang cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy AT junhu cepharanthinesynergizeswithphotodynamictherapyforboostingrosdrivendnadamageandsuppressingmth1asapotentialanticancerstrategy |