Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells
Gastric cancer is a highly metastatic malignant tumor with high morbidity and mortality globally. Recent studies reported that sulfonamide derivatives such as indisulam exhibited inhibitory effects on the viability and migration of cancer cells. However, multiple clinical trials revealed that indisu...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Biomedicine & Pharmacotherapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0753332224001409 |
| _version_ | 1797291849383149568 |
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| author | Changxu Hou Xiaomei Wu Rui Shi Xiaoqi Xing Sheng Tian Morgane Eléouët Chunhua Qiao Jingjing Ma Guoqiang Xu |
| author_facet | Changxu Hou Xiaomei Wu Rui Shi Xiaoqi Xing Sheng Tian Morgane Eléouët Chunhua Qiao Jingjing Ma Guoqiang Xu |
| author_sort | Changxu Hou |
| collection | DOAJ |
| description | Gastric cancer is a highly metastatic malignant tumor with high morbidity and mortality globally. Recent studies reported that sulfonamide derivatives such as indisulam exhibited inhibitory effects on the viability and migration of cancer cells. However, multiple clinical trials revealed that indisulam did not significantly prevent cancer progression due to metastasis and drug resistance. Therefore, it is necessary to discover new potent derivatives to explore alternative therapeutic strategies. Here, we synthesize multiple indisulam derivatives and examine their inhibitory effects on the viability and migration of gastric cancer cells. Among them, compounds SR‐3‐65 and WXM‐1‐170 exhibit better inhibitory effects on the migration of gastric cancer cells than indisulam. Mechanistically, we discover that they could attenuate the PI3K/AKT/GSK-3β/β-catenin signaling pathway and lead to the suppression of epithelial-to-mesenchymal transition (EMT)-related transcription factors. The influence of SR‐3‐65 on the migration of gastric cancer cells is blocked by the PI3K inhibitor LY294002 while SR‐3‐65 and WXM‐1‐170 reverse the effect of PI3K activator 740 Y-P on the migration of gastric cancer cells. Molecular docking and molecular dynamics simulation further confirm that PI3K is the target of SR‐3‐65. Our study unveils a novel mechanism by which SR‐3‐65 and WXM‐1‐170 inhibit the migration of gastric cancer cells. Together with the previous discovery, we reveal that subtle structural change in indisulam results in a striking switch on the molecular targets and their associated signaling pathways for the inhibition of the migration of gastric cancer cells. These findings might provide informative insights for the development of targeted therapy for gastric cancer. |
| first_indexed | 2024-03-07T19:42:46Z |
| format | Article |
| id | doaj.art-a927959fa08345d78f45abe269dfd68d |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-03-07T19:42:46Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-a927959fa08345d78f45abe269dfd68d2024-02-29T05:17:56ZengElsevierBiomedicine & Pharmacotherapy0753-33222024-03-01172116259Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cellsChangxu Hou0Xiaomei Wu1Rui Shi2Xiaoqi Xing3Sheng Tian4Morgane Eléouët5Chunhua Qiao6Jingjing Ma7Guoqiang Xu8Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, ChinaCollege of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, ChinaCollege of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, ChinaCollege of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, ChinaCollege of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, ChinaJiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China; Synbio Technologies Company, BioBay C20, 218 Xinghu Street, Suzhou, Jiangsu, 215123, ChinaCollege of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Corresponding authors.Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, Jiangsu 215123, China; Corresponding authors.Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China; Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu 215123, China; Corresponding author at: Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Province Engineering Research Center of Precision Diagnostics and Therapeutics Development, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Suzhou Key Laboratory of Drug Research for Prevention and Treatment of Hyperlipidemic Diseases, Soochow University, Suzhou, Jiangsu 215123, China.Gastric cancer is a highly metastatic malignant tumor with high morbidity and mortality globally. Recent studies reported that sulfonamide derivatives such as indisulam exhibited inhibitory effects on the viability and migration of cancer cells. However, multiple clinical trials revealed that indisulam did not significantly prevent cancer progression due to metastasis and drug resistance. Therefore, it is necessary to discover new potent derivatives to explore alternative therapeutic strategies. Here, we synthesize multiple indisulam derivatives and examine their inhibitory effects on the viability and migration of gastric cancer cells. Among them, compounds SR‐3‐65 and WXM‐1‐170 exhibit better inhibitory effects on the migration of gastric cancer cells than indisulam. Mechanistically, we discover that they could attenuate the PI3K/AKT/GSK-3β/β-catenin signaling pathway and lead to the suppression of epithelial-to-mesenchymal transition (EMT)-related transcription factors. The influence of SR‐3‐65 on the migration of gastric cancer cells is blocked by the PI3K inhibitor LY294002 while SR‐3‐65 and WXM‐1‐170 reverse the effect of PI3K activator 740 Y-P on the migration of gastric cancer cells. Molecular docking and molecular dynamics simulation further confirm that PI3K is the target of SR‐3‐65. Our study unveils a novel mechanism by which SR‐3‐65 and WXM‐1‐170 inhibit the migration of gastric cancer cells. Together with the previous discovery, we reveal that subtle structural change in indisulam results in a striking switch on the molecular targets and their associated signaling pathways for the inhibition of the migration of gastric cancer cells. These findings might provide informative insights for the development of targeted therapy for gastric cancer.http://www.sciencedirect.com/science/article/pii/S0753332224001409Indisulam derivativesInhibitory effectMigrationGastric cancerPI3KMolecular docking |
| spellingShingle | Changxu Hou Xiaomei Wu Rui Shi Xiaoqi Xing Sheng Tian Morgane Eléouët Chunhua Qiao Jingjing Ma Guoqiang Xu Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells Biomedicine & Pharmacotherapy Indisulam derivatives Inhibitory effect Migration Gastric cancer PI3K Molecular docking |
| title | Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells |
| title_full | Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells |
| title_fullStr | Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells |
| title_full_unstemmed | Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells |
| title_short | Subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells |
| title_sort | subtle structural alteration in indisulam switches the molecular mechanisms for the inhibitory effect on the migration of gastric cancer cells |
| topic | Indisulam derivatives Inhibitory effect Migration Gastric cancer PI3K Molecular docking |
| url | http://www.sciencedirect.com/science/article/pii/S0753332224001409 |
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