Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS‐dependent apoptosis and ferroptosis
Abstract The application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs), such as gefitinib, has shifted lung cancer treatment from empirical chemotherapy to targeted molecular therapy. However, acquired drug resistance is inevitable in almost all non‐small cell lung cance...
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| Format: | Article |
| Language: | English |
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Wiley
2023-07-01
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| Series: | Kaohsiung Journal of Medical Sciences |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/kjm2.12684 |
| _version_ | 1797780841087107072 |
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| author | Xiang‐Yu Lai Yu‐Mei Shi Ming‐Ming Zhou |
| author_facet | Xiang‐Yu Lai Yu‐Mei Shi Ming‐Ming Zhou |
| author_sort | Xiang‐Yu Lai |
| collection | DOAJ |
| description | Abstract The application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs), such as gefitinib, has shifted lung cancer treatment from empirical chemotherapy to targeted molecular therapy. However, acquired drug resistance is inevitable in almost all non‐small cell lung cancer (NSCLC) patients treated with gefitinib. Combined treatment with dihydroartemisinin (DHA) and gefitinib produced a better inhibitory effect on lung adenocarcinoma than gefitinib treatment alone; however, the specific mechanism remains unclear. In this study, we aimed to assess the underlying mechanism of this combination treatment. We prepared gefitinib‐resistant A549 cells and investigated whether apoptosis and ferroptosis were involved in the sensitizing effect of DHA. Treatment with 5 μM gefitinib resulted in rupturing and floatation of A549 cells in the medium, while A549‐GR cells were found to be insusceptible to gefitinib. However, treatment with DHA substantially inhibited the proliferation of A549‐GR cells in a dose‐dependent manner accompanied by increased apoptosis and ferroptosis. The accumulated reactive oxygen species (ROS) was crucial for the inhibitory effect of DHA on A549‐GR cells. Moreover, cellular autophagy was significantly upregulated post‐DHA treatment. The combined treatment of DHA and gefitinib resulted in inhibition of proliferation of A549, H1975, and HCC827 cells, and ROS accumulation and a remarkable induction of apoptosis was observed in A549‐GR cells. DHA significantly induced apoptosis and ferroptosis in a dose‐dependent manner and exhibited high cellular toxicity on A549‐GR cells when combined with gefitinib. |
| first_indexed | 2024-03-12T23:49:30Z |
| format | Article |
| id | doaj.art-948dac18733948da97f31322c92a15f0 |
| institution | Directory Open Access Journal |
| issn | 1607-551X 2410-8650 |
| language | English |
| last_indexed | 2024-03-12T23:49:30Z |
| publishDate | 2023-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Kaohsiung Journal of Medical Sciences |
| spelling | doaj.art-948dac18733948da97f31322c92a15f02023-07-13T17:14:42ZengWileyKaohsiung Journal of Medical Sciences1607-551X2410-86502023-07-0139769970910.1002/kjm2.12684Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS‐dependent apoptosis and ferroptosisXiang‐Yu Lai0Yu‐Mei Shi1Ming‐Ming Zhou2Department of Pharmacy Chongqing University Cancer Hospital Chongqing ChinaDepartment of Medical Oncology Chongqing University Cancer Hospital Chongqing ChinaDepartment of Critical Care Medicine Chongqing University Cancer Hospital Chongqing ChinaAbstract The application of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs), such as gefitinib, has shifted lung cancer treatment from empirical chemotherapy to targeted molecular therapy. However, acquired drug resistance is inevitable in almost all non‐small cell lung cancer (NSCLC) patients treated with gefitinib. Combined treatment with dihydroartemisinin (DHA) and gefitinib produced a better inhibitory effect on lung adenocarcinoma than gefitinib treatment alone; however, the specific mechanism remains unclear. In this study, we aimed to assess the underlying mechanism of this combination treatment. We prepared gefitinib‐resistant A549 cells and investigated whether apoptosis and ferroptosis were involved in the sensitizing effect of DHA. Treatment with 5 μM gefitinib resulted in rupturing and floatation of A549 cells in the medium, while A549‐GR cells were found to be insusceptible to gefitinib. However, treatment with DHA substantially inhibited the proliferation of A549‐GR cells in a dose‐dependent manner accompanied by increased apoptosis and ferroptosis. The accumulated reactive oxygen species (ROS) was crucial for the inhibitory effect of DHA on A549‐GR cells. Moreover, cellular autophagy was significantly upregulated post‐DHA treatment. The combined treatment of DHA and gefitinib resulted in inhibition of proliferation of A549, H1975, and HCC827 cells, and ROS accumulation and a remarkable induction of apoptosis was observed in A549‐GR cells. DHA significantly induced apoptosis and ferroptosis in a dose‐dependent manner and exhibited high cellular toxicity on A549‐GR cells when combined with gefitinib.https://doi.org/10.1002/kjm2.12684DHAEGFR‐TKIsFerroptosisNSCLCROS |
| spellingShingle | Xiang‐Yu Lai Yu‐Mei Shi Ming‐Ming Zhou Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS‐dependent apoptosis and ferroptosis Kaohsiung Journal of Medical Sciences DHA EGFR‐TKIs Ferroptosis NSCLC ROS |
| title | Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS‐dependent apoptosis and ferroptosis |
| title_full | Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS‐dependent apoptosis and ferroptosis |
| title_fullStr | Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS‐dependent apoptosis and ferroptosis |
| title_full_unstemmed | Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS‐dependent apoptosis and ferroptosis |
| title_short | Dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ROS‐dependent apoptosis and ferroptosis |
| title_sort | dihydroartemisinin enhances gefitinib cytotoxicity against lung adenocarcinoma cells by inducing ros dependent apoptosis and ferroptosis |
| topic | DHA EGFR‐TKIs Ferroptosis NSCLC ROS |
| url | https://doi.org/10.1002/kjm2.12684 |
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