c-kit inhibitor masitinib induces reactive oxygen species-dependent apoptosis in c-kit-negative HepG2 cells
Copyright © 2022 Elsevier B.V. All rights reserved..
Tumor-specific growth signal inhibition is a major anticancer strategy. Receptor tyrosine kinases (RTKs) are the most upstream receptors for growth signaling in cancer. Therefore, inhibition of RTKs has been proposed as an efficient therapeutic target. Masitinib, a c-kit inhibitor of the c-kit RTK, was developed to treat mastocytoma in dogs. In humans, however, the antitumor efficacy of masitinib was found to be attenuated against tumor cells with mutations of the c-kit gene. Here, we report that masitinib induced cell death via the intrinsic apoptotic pathway in HepG2, a c-kit-negative hepatocellular carcinoma cell line. In masitinib-treated HepG2 cells, increases in intracellular reactive oxygen species levels, loss of mitochondrial membrane potential, and cleavage of caspase-9 were observed, activating the intrinsic apoptotic pathway. Moreover, the cytotoxicity of masitinib to HepG2 cells was suppressed by treatment with the antioxidant N-acetyl-L-cysteine or a c-Jun N-terminal kinase/stress-activated protein kinase (JNKs) inhibitor. Thus, we demonstrated that the anticancer effects of masitinib are not due to its targeting c-kit, but rather to its targeting the redox balance via the JNK pathway in HepG2 cells. These results suggest that masitinib has the potential to provide a robust antitumor effect in tumor lesions and could also be applied to a broad range of other anticancer therapies.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:931 |
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| Enthalten in: |
European journal of pharmacology - 931(2022) vom: 15. Sept., Seite 175183 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Semba, Yuta [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 07.09.2022 Date Revised 08.09.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejphar.2022.175183 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM344596745 |
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| 520 | |a Tumor-specific growth signal inhibition is a major anticancer strategy. Receptor tyrosine kinases (RTKs) are the most upstream receptors for growth signaling in cancer. Therefore, inhibition of RTKs has been proposed as an efficient therapeutic target. Masitinib, a c-kit inhibitor of the c-kit RTK, was developed to treat mastocytoma in dogs. In humans, however, the antitumor efficacy of masitinib was found to be attenuated against tumor cells with mutations of the c-kit gene. Here, we report that masitinib induced cell death via the intrinsic apoptotic pathway in HepG2, a c-kit-negative hepatocellular carcinoma cell line. In masitinib-treated HepG2 cells, increases in intracellular reactive oxygen species levels, loss of mitochondrial membrane potential, and cleavage of caspase-9 were observed, activating the intrinsic apoptotic pathway. Moreover, the cytotoxicity of masitinib to HepG2 cells was suppressed by treatment with the antioxidant N-acetyl-L-cysteine or a c-Jun N-terminal kinase/stress-activated protein kinase (JNKs) inhibitor. Thus, we demonstrated that the anticancer effects of masitinib are not due to its targeting c-kit, but rather to its targeting the redox balance via the JNK pathway in HepG2 cells. These results suggest that masitinib has the potential to provide a robust antitumor effect in tumor lesions and could also be applied to a broad range of other anticancer therapies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Masitinib | |
| 650 | 4 | |a Mitochondrial apoptosis | |
| 650 | 4 | |a Reactive oxygen species (ROS) | |
| 650 | 4 | |a Receptor tyrosine kinase | |
| 650 | 4 | |a c-Jun N-Terminal kinases (JNKs) | |
| 650 | 7 | |a Benzamides |2 NLM | |
| 650 | 7 | |a Piperidines |2 NLM | |
| 650 | 7 | |a Pyridines |2 NLM | |
| 650 | 7 | |a Reactive Oxygen Species |2 NLM | |
| 650 | 7 | |a Thiazoles |2 NLM | |
| 650 | 7 | |a KIT protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-kit |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a JNK Mitogen-Activated Protein Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.11.24 |2 NLM | |
| 650 | 7 | |a masitinib |2 NLM | |
| 650 | 7 | |a M59NC4E26P |2 NLM | |
| 700 | 1 | |a Yamamoto, Shintaro |e verfasserin |4 aut | |
| 700 | 1 | |a Takahashi, Shunsuke |e verfasserin |4 aut | |
| 700 | 1 | |a Shinomiya, Takahisa |e verfasserin |4 aut | |
| 700 | 1 | |a Nagahara, Yukitoshi |e verfasserin |4 aut | |
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