Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Neoadjuvant chemotherapy (NAC) has become a standard treatment for patients scheduled for surgical resection, but the high rate of postoperative recurrence is a critical problem. Optimization of NAC is desirable to...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/15/1/70 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832588919207624704 |
|---|---|
| author | Keisuke Takemura Kyohei Ikeda Hayato Miyake Yoshio Sogame Hiroaki Yasuda Nobuhiro Okada Kazumi Iwata Junichi Sakagami Kanji Yamaguchi Yoshito Itoh Atsushi Umemura |
| author_facet | Keisuke Takemura Kyohei Ikeda Hayato Miyake Yoshio Sogame Hiroaki Yasuda Nobuhiro Okada Kazumi Iwata Junichi Sakagami Kanji Yamaguchi Yoshito Itoh Atsushi Umemura |
| author_sort | Keisuke Takemura |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Neoadjuvant chemotherapy (NAC) has become a standard treatment for patients scheduled for surgical resection, but the high rate of postoperative recurrence is a critical problem. Optimization of NAC is desirable to reduce postoperative recurrence and achieve long-term survival. However, if a patient’s general condition deteriorates due to NAC toxicity, surgical outcomes may be compromised. Therefore, we aimed to identify drug(s) that can be used in combination with gemcitabine (GEM), a drug widely used for the treatment of PDAC, to inhibit distant metastatic recurrence, particularly after surgery. After several screening steps, ML210, a low molecular weight chemical, was found to suppress the epithelial–mesenchymal transition (EMT) in PDAC cells in combination with GEM. Specifically, low dose ML210 in combination with GEM was sufficient for cell migration without apparent toxicity or cell death. Mechanistically, ML210, which was developed as a glutathione peroxidase 4 (GPX4) inhibitor to induce lipid peroxidation, increased the oxidized lipid concentrations in PDAC cells. The oxidization of the cell membrane lipids may suppress EMT, including cell migration. Since EMT is a major malignant phenotype of PDAC, our findings may lead to the advancement of PDAC therapy, especially in the prevention of postoperative recurrence. |
| format | Article |
| id | doaj-art-9a92eaad21bb43339533f70ee855c035 |
| institution | Kabale University |
| issn | 2218-273X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-9a92eaad21bb43339533f70ee855c0352025-01-24T13:25:04ZengMDPI AGBiomolecules2218-273X2025-01-011517010.3390/biom15010070Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC CellsKeisuke Takemura0Kyohei Ikeda1Hayato Miyake2Yoshio Sogame3Hiroaki Yasuda4Nobuhiro Okada5Kazumi Iwata6Junichi Sakagami7Kanji Yamaguchi8Yoshito Itoh9Atsushi Umemura10Department of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanDepartment of Pharmacology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, JapanPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. Neoadjuvant chemotherapy (NAC) has become a standard treatment for patients scheduled for surgical resection, but the high rate of postoperative recurrence is a critical problem. Optimization of NAC is desirable to reduce postoperative recurrence and achieve long-term survival. However, if a patient’s general condition deteriorates due to NAC toxicity, surgical outcomes may be compromised. Therefore, we aimed to identify drug(s) that can be used in combination with gemcitabine (GEM), a drug widely used for the treatment of PDAC, to inhibit distant metastatic recurrence, particularly after surgery. After several screening steps, ML210, a low molecular weight chemical, was found to suppress the epithelial–mesenchymal transition (EMT) in PDAC cells in combination with GEM. Specifically, low dose ML210 in combination with GEM was sufficient for cell migration without apparent toxicity or cell death. Mechanistically, ML210, which was developed as a glutathione peroxidase 4 (GPX4) inhibitor to induce lipid peroxidation, increased the oxidized lipid concentrations in PDAC cells. The oxidization of the cell membrane lipids may suppress EMT, including cell migration. Since EMT is a major malignant phenotype of PDAC, our findings may lead to the advancement of PDAC therapy, especially in the prevention of postoperative recurrence.https://www.mdpi.com/2218-273X/15/1/70pancreatic ductal adenocarcinomaneoadjuvant chemotherapyepithelial–mesenchymal transitionML210gemcitabine |
| spellingShingle | Keisuke Takemura Kyohei Ikeda Hayato Miyake Yoshio Sogame Hiroaki Yasuda Nobuhiro Okada Kazumi Iwata Junichi Sakagami Kanji Yamaguchi Yoshito Itoh Atsushi Umemura Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells Biomolecules pancreatic ductal adenocarcinoma neoadjuvant chemotherapy epithelial–mesenchymal transition ML210 gemcitabine |
| title | Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells |
| title_full | Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells |
| title_fullStr | Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells |
| title_full_unstemmed | Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells |
| title_short | Epithelial–Mesenchymal Transition Suppression by ML210 Enhances Gemcitabine Anti-Tumor Effects on PDAC Cells |
| title_sort | epithelial mesenchymal transition suppression by ml210 enhances gemcitabine anti tumor effects on pdac cells |
| topic | pancreatic ductal adenocarcinoma neoadjuvant chemotherapy epithelial–mesenchymal transition ML210 gemcitabine |
| url | https://www.mdpi.com/2218-273X/15/1/70 |
| work_keys_str_mv | AT keisuketakemura epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT kyoheiikeda epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT hayatomiyake epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT yoshiosogame epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT hiroakiyasuda epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT nobuhirookada epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT kazumiiwata epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT junichisakagami epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT kanjiyamaguchi epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT yoshitoitoh epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells AT atsushiumemura epithelialmesenchymaltransitionsuppressionbyml210enhancesgemcitabineantitumoreffectsonpdaccells |