Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma

Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Syue-Wei Peng [verfasserIn] Mai-Huong T. Ngo [verfasserIn] Yung-Che Kuo [verfasserIn] Ming-Hao Teng [verfasserIn] Chin-Lin Guo [verfasserIn] Hung-Cheng Lai [verfasserIn] Te-Sheng Chang [verfasserIn] Yen-Hua Huang [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	HCC sorafenib resensitization IGF-1R metabolic change niclosamide organoid

Übergeordnetes Werk:	In: Cancers - MDPI AG, 2010, 15(2023), 3, p 931
Übergeordnetes Werk:	volume:15 ; year:2023 ; number:3, p 931

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3390/cancers15030931

Katalog-ID:	DOAJ080672507

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allfields	10.3390/cancers15030931 doi (DE-627)DOAJ080672507 (DE-599)DOAJdcb37c96b0b84596b5ff8fbfdb7cb723 DE-627 ger DE-627 rakwb eng RC254-282 Syue-Wei Peng verfasserin aut Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC. HCC sorafenib resensitization IGF-1R metabolic change niclosamide organoid Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mai-Huong T. Ngo verfasserin aut Yung-Che Kuo verfasserin aut Ming-Hao Teng verfasserin aut Chin-Lin Guo verfasserin aut Hung-Cheng Lai verfasserin aut Te-Sheng Chang verfasserin aut Yen-Hua Huang verfasserin aut In Cancers MDPI AG, 2010 15(2023), 3, p 931 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:15 year:2023 number:3, p 931 https://doi.org/10.3390/cancers15030931 kostenfrei https://doaj.org/article/dcb37c96b0b84596b5ff8fbfdb7cb723 kostenfrei https://www.mdpi.com/2072-6694/15/3/931 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3, p 931
spelling	10.3390/cancers15030931 doi (DE-627)DOAJ080672507 (DE-599)DOAJdcb37c96b0b84596b5ff8fbfdb7cb723 DE-627 ger DE-627 rakwb eng RC254-282 Syue-Wei Peng verfasserin aut Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC. HCC sorafenib resensitization IGF-1R metabolic change niclosamide organoid Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mai-Huong T. Ngo verfasserin aut Yung-Che Kuo verfasserin aut Ming-Hao Teng verfasserin aut Chin-Lin Guo verfasserin aut Hung-Cheng Lai verfasserin aut Te-Sheng Chang verfasserin aut Yen-Hua Huang verfasserin aut In Cancers MDPI AG, 2010 15(2023), 3, p 931 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:15 year:2023 number:3, p 931 https://doi.org/10.3390/cancers15030931 kostenfrei https://doaj.org/article/dcb37c96b0b84596b5ff8fbfdb7cb723 kostenfrei https://www.mdpi.com/2072-6694/15/3/931 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3, p 931
allfields_unstemmed	10.3390/cancers15030931 doi (DE-627)DOAJ080672507 (DE-599)DOAJdcb37c96b0b84596b5ff8fbfdb7cb723 DE-627 ger DE-627 rakwb eng RC254-282 Syue-Wei Peng verfasserin aut Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC. HCC sorafenib resensitization IGF-1R metabolic change niclosamide organoid Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mai-Huong T. Ngo verfasserin aut Yung-Che Kuo verfasserin aut Ming-Hao Teng verfasserin aut Chin-Lin Guo verfasserin aut Hung-Cheng Lai verfasserin aut Te-Sheng Chang verfasserin aut Yen-Hua Huang verfasserin aut In Cancers MDPI AG, 2010 15(2023), 3, p 931 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:15 year:2023 number:3, p 931 https://doi.org/10.3390/cancers15030931 kostenfrei https://doaj.org/article/dcb37c96b0b84596b5ff8fbfdb7cb723 kostenfrei https://www.mdpi.com/2072-6694/15/3/931 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3, p 931
allfieldsGer	10.3390/cancers15030931 doi (DE-627)DOAJ080672507 (DE-599)DOAJdcb37c96b0b84596b5ff8fbfdb7cb723 DE-627 ger DE-627 rakwb eng RC254-282 Syue-Wei Peng verfasserin aut Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC. HCC sorafenib resensitization IGF-1R metabolic change niclosamide organoid Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mai-Huong T. Ngo verfasserin aut Yung-Che Kuo verfasserin aut Ming-Hao Teng verfasserin aut Chin-Lin Guo verfasserin aut Hung-Cheng Lai verfasserin aut Te-Sheng Chang verfasserin aut Yen-Hua Huang verfasserin aut In Cancers MDPI AG, 2010 15(2023), 3, p 931 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:15 year:2023 number:3, p 931 https://doi.org/10.3390/cancers15030931 kostenfrei https://doaj.org/article/dcb37c96b0b84596b5ff8fbfdb7cb723 kostenfrei https://www.mdpi.com/2072-6694/15/3/931 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3, p 931
allfieldsSound	10.3390/cancers15030931 doi (DE-627)DOAJ080672507 (DE-599)DOAJdcb37c96b0b84596b5ff8fbfdb7cb723 DE-627 ger DE-627 rakwb eng RC254-282 Syue-Wei Peng verfasserin aut Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC. HCC sorafenib resensitization IGF-1R metabolic change niclosamide organoid Neoplasms. Tumors. Oncology. Including cancer and carcinogens Mai-Huong T. Ngo verfasserin aut Yung-Che Kuo verfasserin aut Ming-Hao Teng verfasserin aut Chin-Lin Guo verfasserin aut Hung-Cheng Lai verfasserin aut Te-Sheng Chang verfasserin aut Yen-Hua Huang verfasserin aut In Cancers MDPI AG, 2010 15(2023), 3, p 931 (DE-627)614095670 (DE-600)2527080-1 20726694 nnns volume:15 year:2023 number:3, p 931 https://doi.org/10.3390/cancers15030931 kostenfrei https://doaj.org/article/dcb37c96b0b84596b5ff8fbfdb7cb723 kostenfrei https://www.mdpi.com/2072-6694/15/3/931 kostenfrei https://doaj.org/toc/2072-6694 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2023 3, p 931
language	English
source	In Cancers 15(2023), 3, p 931 volume:15 year:2023 number:3, p 931
sourceStr	In Cancers 15(2023), 3, p 931 volume:15 year:2023 number:3, p 931
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	HCC sorafenib resensitization IGF-1R metabolic change niclosamide organoid Neoplasms. Tumors. Oncology. Including cancer and carcinogens
isfreeaccess_bool	true
container_title	Cancers
authorswithroles_txt_mv	Syue-Wei Peng @@aut@@ Mai-Huong T. Ngo @@aut@@ Yung-Che Kuo @@aut@@ Ming-Hao Teng @@aut@@ Chin-Lin Guo @@aut@@ Hung-Cheng Lai @@aut@@ Te-Sheng Chang @@aut@@ Yen-Hua Huang @@aut@@
publishDateDaySort_date	2023-01-01T00:00:00Z
hierarchy_top_id	614095670
id	DOAJ080672507
language_de	englisch
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callnumber-first	R - Medicine
author	Syue-Wei Peng
spellingShingle	Syue-Wei Peng misc RC254-282 misc HCC sorafenib resensitization misc IGF-1R misc metabolic change misc niclosamide misc organoid misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma
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topic_title	RC254-282 Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma HCC sorafenib resensitization IGF-1R metabolic change niclosamide organoid
topic	misc RC254-282 misc HCC sorafenib resensitization misc IGF-1R misc metabolic change misc niclosamide misc organoid misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_unstemmed	misc RC254-282 misc HCC sorafenib resensitization misc IGF-1R misc metabolic change misc niclosamide misc organoid misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
topic_browse	misc RC254-282 misc HCC sorafenib resensitization misc IGF-1R misc metabolic change misc niclosamide misc organoid misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens
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title	Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma
ctrlnum	(DE-627)DOAJ080672507 (DE-599)DOAJdcb37c96b0b84596b5ff8fbfdb7cb723
title_full	Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma
author_sort	Syue-Wei Peng
journal	Cancers
journalStr	Cancers
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author_browse	Syue-Wei Peng Mai-Huong T. Ngo Yung-Che Kuo Ming-Hao Teng Chin-Lin Guo Hung-Cheng Lai Te-Sheng Chang Yen-Hua Huang
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class	RC254-282
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author-letter	Syue-Wei Peng
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title_sort	niclosamide revitalizes sorafenib through insulin-like growth factor 1 receptor (igf-1r)/stemness and metabolic changes in hepatocellular carcinoma
callnumber	RC254-282
title_auth	Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma
abstract	Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC.
abstractGer	Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC.
abstract_unstemmed	Sorafenib is the first approved systemic targeting agent for advanced HCC; however, when used alone, drug resistance can result in considerably reduced efficacy. Here, we demonstrate that niclosamide, an antihelminthic agent approved by the US Food and Drug Administration, can be repurposed to increase sorafenib sensitivity in sorafenib-resistant HCC cells. We generated sorafenib-resistant HCC cell lines (HepG2215_R and Hep3B_R) with elevated IGF-1R levels and strong properties in terms of stemness and epithelial–mesenchymal transition. Niclosamide was found to increase sorafenib sensitivity effectively in both cell lines and their organoids. The underlying mechanism involves the modulation of cancer stemness, IGF-1R/p-IGF1R/OCT4, and metabolic changes. The combination of sorafenib and niclosamide, but not linsitinib, effectively suppressed the IGF-1R/OCT4 expressions, yielded a synergistic combination index (CI), and attenuated stemness-related properties such as secondary tumor sphere formation and cell migration in sorafenib-resistant HCC cells. Notably, niclosamide significantly suppressed the sorafenib-induced IGF-1R phosphorylation prompted by IGF-1 treatment. Niclosamide effectively downregulated the sorafenib-induced gene expression associated with glycolysis (<i<GLUT1</i<, <i<HK2</i<, <i<LDHA</i<, and <i<PEPCK</i<), stemness (<i<OCT4</i<), and drug resistance (<i<ABCG2</i<) and enhanced the ability of sorafenib to reduce the mitochondrial membrane potential in vitro. The synergistic effect of a combination of niclosamide and sorafenib in vivo was further demonstrated by the decreased tumor size and tumor volume resulting from apoptosis regulation. Our results suggest that niclosamide can enhance sorafenib sensitivity in sorafenib-resistant HCC cells through IGF-1R/stemness regulation and metabolic changes. Our findings highlight a practical clinical strategy for enhancing sorafenib sensitivity in HCC.
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title_short	Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma
url	https://doi.org/10.3390/cancers15030931 https://doaj.org/article/dcb37c96b0b84596b5ff8fbfdb7cb723 https://www.mdpi.com/2072-6694/15/3/931 https://doaj.org/toc/2072-6694
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Niclosamide Revitalizes Sorafenib through Insulin-like Growth Factor 1 Receptor (IGF-1R)/Stemness and Metabolic Changes in Hepatocellular Carcinoma

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