AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Eslam E. Abd El-Fattah [verfasserIn] Sameh Saber [verfasserIn] Mahmoud E. Youssef [verfasserIn] Hanan Eissa [verfasserIn] Eman El-Ahwany [verfasserIn] Noha A. Amin [verfasserIn] Mohammed Alqarni [verfasserIn] Gaber El-Saber Batiha [verfasserIn] Ahmad J. Obaidullah [verfasserIn] Mohamed M.Y. Kaddah [verfasserIn] Ahmed Gaafar Ahmed Gaafar [verfasserIn] Ahmed A.E. Mourad [verfasserIn] Gomaa Mostafa-Hedeab [verfasserIn] Amir Mohamed Abdelhamid [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	hepatocellular carcinoma sitagliptin HIF-1α Akt AMPKα mTOR

Übergeordnetes Werk:	In: Frontiers in Pharmacology - Frontiers Media S.A., 2010, 12(2022)
Übergeordnetes Werk:	volume:12 ; year:2022

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.3389/fphar.2021.720173

Katalog-ID:	DOAJ074114913

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650		4	\|a hepatocellular carcinoma
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allfields	10.3389/fphar.2021.720173 doi (DE-627)DOAJ074114913 (DE-599)DOAJbef7df31734f402aafc87c7e96643e3f DE-627 ger DE-627 rakwb eng RM1-950 Eslam E. Abd El-Fattah verfasserin aut AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC. hepatocellular carcinoma sitagliptin HIF-1α Akt AMPKα mTOR Therapeutics. Pharmacology Sameh Saber verfasserin aut Mahmoud E. Youssef verfasserin aut Hanan Eissa verfasserin aut Eman El-Ahwany verfasserin aut Noha A. Amin verfasserin aut Mohammed Alqarni verfasserin aut Gaber El-Saber Batiha verfasserin aut Ahmad J. Obaidullah verfasserin aut Ahmad J. Obaidullah verfasserin aut Mohamed M.Y. Kaddah verfasserin aut Ahmed Gaafar Ahmed Gaafar verfasserin aut Ahmed A.E. Mourad verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Amir Mohamed Abdelhamid verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2022 https://doi.org/10.3389/fphar.2021.720173 kostenfrei https://doaj.org/article/bef7df31734f402aafc87c7e96643e3f kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.720173/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2003 GBV_ILN_2014 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 12 2022
spelling	10.3389/fphar.2021.720173 doi (DE-627)DOAJ074114913 (DE-599)DOAJbef7df31734f402aafc87c7e96643e3f DE-627 ger DE-627 rakwb eng RM1-950 Eslam E. Abd El-Fattah verfasserin aut AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC. hepatocellular carcinoma sitagliptin HIF-1α Akt AMPKα mTOR Therapeutics. Pharmacology Sameh Saber verfasserin aut Mahmoud E. Youssef verfasserin aut Hanan Eissa verfasserin aut Eman El-Ahwany verfasserin aut Noha A. Amin verfasserin aut Mohammed Alqarni verfasserin aut Gaber El-Saber Batiha verfasserin aut Ahmad J. Obaidullah verfasserin aut Ahmad J. Obaidullah verfasserin aut Mohamed M.Y. Kaddah verfasserin aut Ahmed Gaafar Ahmed Gaafar verfasserin aut Ahmed A.E. Mourad verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Amir Mohamed Abdelhamid verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2022 https://doi.org/10.3389/fphar.2021.720173 kostenfrei https://doaj.org/article/bef7df31734f402aafc87c7e96643e3f kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.720173/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2003 GBV_ILN_2014 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 12 2022
allfields_unstemmed	10.3389/fphar.2021.720173 doi (DE-627)DOAJ074114913 (DE-599)DOAJbef7df31734f402aafc87c7e96643e3f DE-627 ger DE-627 rakwb eng RM1-950 Eslam E. Abd El-Fattah verfasserin aut AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC. hepatocellular carcinoma sitagliptin HIF-1α Akt AMPKα mTOR Therapeutics. Pharmacology Sameh Saber verfasserin aut Mahmoud E. Youssef verfasserin aut Hanan Eissa verfasserin aut Eman El-Ahwany verfasserin aut Noha A. Amin verfasserin aut Mohammed Alqarni verfasserin aut Gaber El-Saber Batiha verfasserin aut Ahmad J. Obaidullah verfasserin aut Ahmad J. Obaidullah verfasserin aut Mohamed M.Y. Kaddah verfasserin aut Ahmed Gaafar Ahmed Gaafar verfasserin aut Ahmed A.E. Mourad verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Amir Mohamed Abdelhamid verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2022 https://doi.org/10.3389/fphar.2021.720173 kostenfrei https://doaj.org/article/bef7df31734f402aafc87c7e96643e3f kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.720173/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2003 GBV_ILN_2014 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 12 2022
allfieldsGer	10.3389/fphar.2021.720173 doi (DE-627)DOAJ074114913 (DE-599)DOAJbef7df31734f402aafc87c7e96643e3f DE-627 ger DE-627 rakwb eng RM1-950 Eslam E. Abd El-Fattah verfasserin aut AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC. hepatocellular carcinoma sitagliptin HIF-1α Akt AMPKα mTOR Therapeutics. Pharmacology Sameh Saber verfasserin aut Mahmoud E. Youssef verfasserin aut Hanan Eissa verfasserin aut Eman El-Ahwany verfasserin aut Noha A. Amin verfasserin aut Mohammed Alqarni verfasserin aut Gaber El-Saber Batiha verfasserin aut Ahmad J. Obaidullah verfasserin aut Ahmad J. Obaidullah verfasserin aut Mohamed M.Y. Kaddah verfasserin aut Ahmed Gaafar Ahmed Gaafar verfasserin aut Ahmed A.E. Mourad verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Amir Mohamed Abdelhamid verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2022 https://doi.org/10.3389/fphar.2021.720173 kostenfrei https://doaj.org/article/bef7df31734f402aafc87c7e96643e3f kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.720173/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2003 GBV_ILN_2014 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 12 2022
allfieldsSound	10.3389/fphar.2021.720173 doi (DE-627)DOAJ074114913 (DE-599)DOAJbef7df31734f402aafc87c7e96643e3f DE-627 ger DE-627 rakwb eng RM1-950 Eslam E. Abd El-Fattah verfasserin aut AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC. hepatocellular carcinoma sitagliptin HIF-1α Akt AMPKα mTOR Therapeutics. Pharmacology Sameh Saber verfasserin aut Mahmoud E. Youssef verfasserin aut Hanan Eissa verfasserin aut Eman El-Ahwany verfasserin aut Noha A. Amin verfasserin aut Mohammed Alqarni verfasserin aut Gaber El-Saber Batiha verfasserin aut Ahmad J. Obaidullah verfasserin aut Ahmad J. Obaidullah verfasserin aut Mohamed M.Y. Kaddah verfasserin aut Ahmed Gaafar Ahmed Gaafar verfasserin aut Ahmed A.E. Mourad verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Gomaa Mostafa-Hedeab verfasserin aut Amir Mohamed Abdelhamid verfasserin aut In Frontiers in Pharmacology Frontiers Media S.A., 2010 12(2022) (DE-627)642889392 (DE-600)2587355-6 16639812 nnns volume:12 year:2022 https://doi.org/10.3389/fphar.2021.720173 kostenfrei https://doaj.org/article/bef7df31734f402aafc87c7e96643e3f kostenfrei https://www.frontiersin.org/articles/10.3389/fphar.2021.720173/full kostenfrei https://doaj.org/toc/1663-9812 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 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_2003 GBV_ILN_2014 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 12 2022
language	English
source	In Frontiers in Pharmacology 12(2022) volume:12 year:2022
sourceStr	In Frontiers in Pharmacology 12(2022) volume:12 year:2022
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	hepatocellular carcinoma sitagliptin HIF-1α Akt AMPKα mTOR Therapeutics. Pharmacology
isfreeaccess_bool	true
container_title	Frontiers in Pharmacology
authorswithroles_txt_mv	Eslam E. Abd El-Fattah @@aut@@ Sameh Saber @@aut@@ Mahmoud E. Youssef @@aut@@ Hanan Eissa @@aut@@ Eman El-Ahwany @@aut@@ Noha A. Amin @@aut@@ Mohammed Alqarni @@aut@@ Gaber El-Saber Batiha @@aut@@ Ahmad J. Obaidullah @@aut@@ Mohamed M.Y. Kaddah @@aut@@ Ahmed Gaafar Ahmed Gaafar @@aut@@ Ahmed A.E. Mourad @@aut@@ Gomaa Mostafa-Hedeab @@aut@@ Amir Mohamed Abdelhamid @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	642889392
id	DOAJ074114913
language_de	englisch
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callnumber-first	R - Medicine
author	Eslam E. Abd El-Fattah
spellingShingle	Eslam E. Abd El-Fattah misc RM1-950 misc hepatocellular carcinoma misc sitagliptin misc HIF-1α misc Akt misc AMPKα misc mTOR misc Therapeutics. Pharmacology AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma
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topic_title	RM1-950 AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma hepatocellular carcinoma sitagliptin HIF-1α Akt AMPKα mTOR
topic	misc RM1-950 misc hepatocellular carcinoma misc sitagliptin misc HIF-1α misc Akt misc AMPKα misc mTOR misc Therapeutics. Pharmacology
topic_unstemmed	misc RM1-950 misc hepatocellular carcinoma misc sitagliptin misc HIF-1α misc Akt misc AMPKα misc mTOR misc Therapeutics. Pharmacology
topic_browse	misc RM1-950 misc hepatocellular carcinoma misc sitagliptin misc HIF-1α misc Akt misc AMPKα misc mTOR misc Therapeutics. Pharmacology
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title	AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma
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title_full	AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma
author_sort	Eslam E. Abd El-Fattah
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author_browse	Eslam E. Abd El-Fattah Sameh Saber Mahmoud E. Youssef Hanan Eissa Eman El-Ahwany Noha A. Amin Mohammed Alqarni Gaber El-Saber Batiha Ahmad J. Obaidullah Mohamed M.Y. Kaddah Ahmed Gaafar Ahmed Gaafar Ahmed A.E. Mourad Gomaa Mostafa-Hedeab Amir Mohamed Abdelhamid
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author-letter	Eslam E. Abd El-Fattah
doi_str_mv	10.3389/fphar.2021.720173
author2-role	verfasserin
title_sort	akt-ampkα-mtor-dependent hif-1α activation is a new therapeutic target for cancer treatment: a novel approach to repositioning the antidiabetic drug sitagliptin for the management of hepatocellular carcinoma
callnumber	RM1-950
title_auth	AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma
abstract	HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.
abstractGer	HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.
abstract_unstemmed	HIF-1α is a key factor promoting the development of hepatocellular carcinoma (HCC). As well, AKT-AMPKα-mTOR signaling is a promising target for cancer therapy. Yet, the AKT-AMPKα-mTOR-dependent activation of HIF-1α has not been studied in livers with HCC. In addition, the mechanisms underlying the potential antineoplastic effects of sitagliptin (STGPT), an antidiabetic agent, have not yet been elucidated. For that purpose, the N-nitrosodiethylamine (NDEA)-induced HCC mouse model was used in the present study using a dose of 100 mg/kg/week, i.p., for 8 weeks. NDEA-induced HCC mice received STGPT 20, 40, or 80 mg/kg starting on day 61 up to day 120. The present study revealed that STGPT inhibited HIF-1α activation via the interference with the AKT-AMPKα-mTOR axis and the interruption of IKKβ, P38α, and ERK1/2 signals as well. Accordingly, STGPT prolonged the survival, restored the histological features and improved liver function. Additionally, STGPT inhibited angiogenesis, as revealed by a significant downregulation in the VEGF and mRNA expression of CD309 with concomitant inhibition of tissue invasion was evident by an increased ratio of TIMP-1/MMP-2. STGPT exhibited apoptotic stimulatory effect as indicated upon calculating the BCL-2/Bax ratio and by the gene expression of p53. The decrease in AFP and liver index calculation, gene expression of Ki-67 confirmed the antiproliferative activity of STGPT. The anti-inflammatory potential was revealed by the decreased TNF-α level and the downregulation of MCP-1 gene expression. Moreover, an antifibrotic potential was supported by lower levels of TGF-β. These effects appear to be GLP1R-independent. The present study provides a potential basis for repurposing STGPT for the inhibition of HCC progression. Since STGPT is unlikely to cause hypoglycemia, it may be promising as monotherapy or adjuvant therapy to treat diabetic or even normoglycemic patients with HCC.
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title_short	AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma
url	https://doi.org/10.3389/fphar.2021.720173 https://doaj.org/article/bef7df31734f402aafc87c7e96643e3f https://www.frontiersin.org/articles/10.3389/fphar.2021.720173/full https://doaj.org/toc/1663-9812
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AKT-AMPKα-mTOR-dependent HIF-1α Activation is a New Therapeutic Target for Cancer Treatment: A Novel Approach to Repositioning the Antidiabetic Drug Sitagliptin for the Management of Hepatocellular Carcinoma

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