Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK
Abstract Treating colorectal cancer (CRC) poses challenges due to the lack of specific molecular targets. Although oxaliplatin (Ox) is commonly used to treat CRC, resistance frequently develops, necessitating the discovery of new therapeutics. This study explored the anticancer effects of Isoalantol...
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Nature Portfolio
2025-04-01
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| Online Access: | https://doi.org/10.1038/s41598-025-98499-7 |
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| author | Seung-On Lee Sang Hoon Joo Na Yeong Lee Seung-Sik Cho Goo Yoon Ki-Taek Kim Yung Hyun Choi Jin Woo Park Joon-Seok Choi Jung-Hyun Shim |
| author_facet | Seung-On Lee Sang Hoon Joo Na Yeong Lee Seung-Sik Cho Goo Yoon Ki-Taek Kim Yung Hyun Choi Jin Woo Park Joon-Seok Choi Jung-Hyun Shim |
| author_sort | Seung-On Lee |
| collection | DOAJ |
| description | Abstract Treating colorectal cancer (CRC) poses challenges due to the lack of specific molecular targets. Although oxaliplatin (Ox) is commonly used to treat CRC, resistance frequently develops, necessitating the discovery of new therapeutics. This study explored the anticancer effects of Isoalantolactone (IAL) on human CRC cells HCT116 and Ox-resistant HCT116 (HCT116-OxR). Apoptosis, ROS generation, cell cycle distribution, mitochondrial membrane potential (MMP), and caspase activation were assessed through flow cytometry. Protein levels were determined by Western blot analysis. IAL reduced cell viability, measured by MTT assay, and inhibited anchorage-independent colony formation in CRC cells in a time- and concentration-dependent manner. The IC50 values for 48 h of incubation were below 10 µM. Annexin V/7-AAD double staining demonstrated that IAL induced apoptosis in HCT116 and HCT116-OxR cells, and Western blot analysis confirmed increased phosphorylation of JNK and p38 mitogen-activated protein kinase (MAPK). The inhibition of these kinases by SP600125 or SB203580 blocked the antiproliferative effects of IAL. Additionally, IAL triggered ROS generation and disrupted mitochondrial membranes, leading to caspase activation. Pretreatment with N-acetylcysteine (NAC) or Z-VAD-FMK inhibited the antiproliferative effects of IAL, highlighting the crucial roles of ROS generation and caspase activation in IAL-induced apoptosis in CRC cells. In summary, IAL exhibited anticancer effects in CRC cells by inducing apoptosis by elevating ROS level and activating JNK and p38 MAPK. These findings warrant further study to evaluate the therapeutic potential of IAL in treating CRC with various resistances. |
| format | Article |
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| issn | 2045-2322 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-b2b315a22b6a4bd597044c557ebf64e82025-08-20T01:47:29ZengNature PortfolioScientific Reports2045-23222025-04-0115111210.1038/s41598-025-98499-7Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPKSeung-On Lee0Sang Hoon Joo1Na Yeong Lee2Seung-Sik Cho3Goo Yoon4Ki-Taek Kim5Yung Hyun Choi6Jin Woo Park7Joon-Seok Choi8Jung-Hyun Shim9Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National UniversityDepartment of Pharmacy, College of Pharmacy, Daegu Catholic UniversityDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National UniversityDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National UniversityDepartment of Pharmacy, College of Pharmacy, Mokpo National UniversityDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National UniversityDepartment of Biochemistry, College of Korean Medicine, Dong-Eui UniversityDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National UniversityDepartment of Pharmacy, College of Pharmacy, Daegu Catholic UniversityDepartment of Biomedicine, Health & Life Convergence Sciences, BK21 Four, College of Pharmacy, Mokpo National UniversityAbstract Treating colorectal cancer (CRC) poses challenges due to the lack of specific molecular targets. Although oxaliplatin (Ox) is commonly used to treat CRC, resistance frequently develops, necessitating the discovery of new therapeutics. This study explored the anticancer effects of Isoalantolactone (IAL) on human CRC cells HCT116 and Ox-resistant HCT116 (HCT116-OxR). Apoptosis, ROS generation, cell cycle distribution, mitochondrial membrane potential (MMP), and caspase activation were assessed through flow cytometry. Protein levels were determined by Western blot analysis. IAL reduced cell viability, measured by MTT assay, and inhibited anchorage-independent colony formation in CRC cells in a time- and concentration-dependent manner. The IC50 values for 48 h of incubation were below 10 µM. Annexin V/7-AAD double staining demonstrated that IAL induced apoptosis in HCT116 and HCT116-OxR cells, and Western blot analysis confirmed increased phosphorylation of JNK and p38 mitogen-activated protein kinase (MAPK). The inhibition of these kinases by SP600125 or SB203580 blocked the antiproliferative effects of IAL. Additionally, IAL triggered ROS generation and disrupted mitochondrial membranes, leading to caspase activation. Pretreatment with N-acetylcysteine (NAC) or Z-VAD-FMK inhibited the antiproliferative effects of IAL, highlighting the crucial roles of ROS generation and caspase activation in IAL-induced apoptosis in CRC cells. In summary, IAL exhibited anticancer effects in CRC cells by inducing apoptosis by elevating ROS level and activating JNK and p38 MAPK. These findings warrant further study to evaluate the therapeutic potential of IAL in treating CRC with various resistances.https://doi.org/10.1038/s41598-025-98499-7IsoalantolactoneApoptosisColorectal cancerOxaliplatinReactive oxygen speciesJNK/p38 MAPK |
| spellingShingle | Seung-On Lee Sang Hoon Joo Na Yeong Lee Seung-Sik Cho Goo Yoon Ki-Taek Kim Yung Hyun Choi Jin Woo Park Joon-Seok Choi Jung-Hyun Shim Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK Scientific Reports Isoalantolactone Apoptosis Colorectal cancer Oxaliplatin Reactive oxygen species JNK/p38 MAPK |
| title | Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK |
| title_full | Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK |
| title_fullStr | Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK |
| title_full_unstemmed | Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK |
| title_short | Isoalantolactone induces the apoptosis of oxaliplatin-resistant human colorectal cancer cells mediated by ROS generation and activation of JNK and p38 MAPK |
| title_sort | isoalantolactone induces the apoptosis of oxaliplatin resistant human colorectal cancer cells mediated by ros generation and activation of jnk and p38 mapk |
| topic | Isoalantolactone Apoptosis Colorectal cancer Oxaliplatin Reactive oxygen species JNK/p38 MAPK |
| url | https://doi.org/10.1038/s41598-025-98499-7 |
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