Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells
Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of chemoresistant cells represents a major challenge in chemotherapy. Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epide...
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MDPI AG
2024-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/1/274 |
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| author | Ye Jin Lim Hee Su Kim Seunghee Bae Kyeong A So Tae Jin Kim Jae Ho Lee |
| author_facet | Ye Jin Lim Hee Su Kim Seunghee Bae Kyeong A So Tae Jin Kim Jae Ho Lee |
| author_sort | Ye Jin Lim |
| collection | DOAJ |
| description | Paclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of chemoresistant cells represents a major challenge in chemotherapy. Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity. Additionally, we confirmed that dacomitinib inhibits chemoresistance in paclitaxel-resistant ovarian cancer HeyA8-MDR cells. Collectively, our research indicated that dacomitinib effectively resensitized paclitaxel in SKOV3-TR cells by inhibiting EGFR signaling and elevating intracellular ROS levels. |
| first_indexed | 2024-03-08T15:01:45Z |
| format | Article |
| id | doaj.art-c75359f901a049fdac6add1dea4327d2 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-08T15:01:45Z |
| publishDate | 2024-01-01 |
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| series | Molecules |
| spelling | doaj.art-c75359f901a049fdac6add1dea4327d22024-01-10T15:04:42ZengMDPI AGMolecules1420-30492024-01-0129127410.3390/molecules29010274Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR CellsYe Jin Lim0Hee Su Kim1Seunghee Bae2Kyeong A So3Tae Jin Kim4Jae Ho Lee5Department of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of KoreaDepartment of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of KoreaDepartment of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of KoreaDepartment of Obstetrics and Gynecology, Konkuk University School of Medicine, Seoul 05030, Republic of KoreaDepartment of Obstetrics and Gynecology, Konkuk University School of Medicine, Seoul 05030, Republic of KoreaDepartment of Cosmetics Engineering, Konkuk University, 120 Neungdong-ro, Seoul 05029, Republic of KoreaPaclitaxel is still used as a standard first-line treatment for ovarian cancer. Although paclitaxel is effective for many types of cancer, the emergence of chemoresistant cells represents a major challenge in chemotherapy. Our study aimed to analyze the cellular mechanism of dacomitinib, a pan-epidermal growth factor receptor (EGFR) inhibitor, which resensitized paclitaxel and induced cell cytotoxicity in paclitaxel-resistant ovarian cancer SKOV3-TR cells. We investigated the significant reduction in cell viability cotreated with dacomitinib and paclitaxel by WST-1 assay and flow cytometry analysis. Dacomitinib inhibited EGFR family proteins, including EGFR and HER2, as well as its downstream signaling proteins, including AKT, STAT3, ERK, and p38. In addition, dacomitinib inhibited the phosphorylation of Bad, and combination treatment with paclitaxel effectively suppressed the expression of Mcl-1. A 2′-7′-dichlorodihydrofluorescein diacetate (DCFH-DA) assay revealed a substantial elevation in cellular reactive oxygen species (ROS) levels in SKOV3-TR cells cotreated with dacomitinib and paclitaxel, which subsequently mediated cell cytotoxicity. Additionally, we confirmed that dacomitinib inhibits chemoresistance in paclitaxel-resistant ovarian cancer HeyA8-MDR cells. Collectively, our research indicated that dacomitinib effectively resensitized paclitaxel in SKOV3-TR cells by inhibiting EGFR signaling and elevating intracellular ROS levels.https://www.mdpi.com/1420-3049/29/1/274dacomitinibpan-EGFR inhibitorovarian cancerpaclitaxel-resistancereactive oxygen species |
| spellingShingle | Ye Jin Lim Hee Su Kim Seunghee Bae Kyeong A So Tae Jin Kim Jae Ho Lee Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells Molecules dacomitinib pan-EGFR inhibitor ovarian cancer paclitaxel-resistance reactive oxygen species |
| title | Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells |
| title_full | Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells |
| title_fullStr | Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells |
| title_full_unstemmed | Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells |
| title_short | Pan-EGFR Inhibitor Dacomitinib Resensitizes Paclitaxel and Induces Apoptosis via Elevating Intracellular ROS Levels in Ovarian Cancer SKOV3-TR Cells |
| title_sort | pan egfr inhibitor dacomitinib resensitizes paclitaxel and induces apoptosis via elevating intracellular ros levels in ovarian cancer skov3 tr cells |
| topic | dacomitinib pan-EGFR inhibitor ovarian cancer paclitaxel-resistance reactive oxygen species |
| url | https://www.mdpi.com/1420-3049/29/1/274 |
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