Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia

The current study investigated the role of combination therapy with voacamine and vincristine in preventing mammary gland carcinoma through prolyl hydroxylase-2 activation. Prolyl hydroxylase-2 activation leads to the downregulation of hypoxia-inducible factor-1α and fatty acid synthase. Overexpress...

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Autores principales:	Lakhveer Singh, Subhadeep Roy, Anurag Kumar, Shubham Rastogi, Dinesh Kumar, Mohd. Nazam Ansari, Abdulaziz S. Saeedan, Manjari Singh, Gaurav Kaithwas
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	mammary gland carcinoma hypoxia inducible factor-1α (HIF-1α) fatty acid synthase (FASN) prolyl hydroxylase-2 voacamine repurposable drugs Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1b7ff98ce0c348bf9a53455e26809de0
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spelling	oai:doaj.org-article:1b7ff98ce0c348bf9a53455e26809de02021-11-18T09:31:29ZRepurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia2296-634X10.3389/fcell.2021.736910https://doaj.org/article/1b7ff98ce0c348bf9a53455e26809de02021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.736910/fullhttps://doaj.org/toc/2296-634XThe current study investigated the role of combination therapy with voacamine and vincristine in preventing mammary gland carcinoma through prolyl hydroxylase-2 activation. Prolyl hydroxylase-2 activation leads to the downregulation of hypoxia-inducible factor-1α and fatty acid synthase. Overexpression of hypoxia-inducible factor-1α and fatty acid synthase has been previously reported in solid tumors of the mammary gland. After screening a battery of natural compounds similar to vincristine, voacamine was selected as a possible prolyl hydroxylase-2 activator, and its activity was evaluated using a 7,12-dimethylbenz[a]anthracene-induced rat model. The combination therapy was evaluated for cardiac toxicity using a hemodynamic profile. Angiogenic markers were evaluated by carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity using hematoxylin and eosin staining. The antioxidant potential was delineated using oxidative stress markers. The serum metabolomic profile was studied using NMR spectroscopy, and the disruption of fatty acids was evaluated using gas chromatography. Western blotting of proteins involved in hypoxic pathways was performed to decipher the action of therapy at the molecular level. Immunoblotting analysis validated that combination therapy has potential toss with prolyl hydroxylase-2 activity and thus initiates proteolytic degradation of hypoxia-inducible factor-1α and its consequent effects. Combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells. The present study explored the role of voacamine inactivation of prolyl hydroxylase-2, which can decrease the overexpression of hypoxia-inducible factor-1α and fatty acid synthase in mammary gland carcinoma cells.Lakhveer SinghSubhadeep RoyAnurag KumarShubham RastogiDinesh KumarMohd. Nazam AnsariAbdulaziz S. SaeedanManjari SinghGaurav KaithwasFrontiers Media S.A.articlemammary gland carcinomahypoxia inducible factor-1α (HIF-1α)fatty acid synthase (FASN)prolyl hydroxylase-2voacaminerepurposable drugsBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	mammary gland carcinoma hypoxia inducible factor-1α (HIF-1α) fatty acid synthase (FASN) prolyl hydroxylase-2 voacamine repurposable drugs Biology (General) QH301-705.5
spellingShingle	mammary gland carcinoma hypoxia inducible factor-1α (HIF-1α) fatty acid synthase (FASN) prolyl hydroxylase-2 voacamine repurposable drugs Biology (General) QH301-705.5 Lakhveer Singh Subhadeep Roy Anurag Kumar Shubham Rastogi Dinesh Kumar Mohd. Nazam Ansari Abdulaziz S. Saeedan Manjari Singh Gaurav Kaithwas Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia
description	The current study investigated the role of combination therapy with voacamine and vincristine in preventing mammary gland carcinoma through prolyl hydroxylase-2 activation. Prolyl hydroxylase-2 activation leads to the downregulation of hypoxia-inducible factor-1α and fatty acid synthase. Overexpression of hypoxia-inducible factor-1α and fatty acid synthase has been previously reported in solid tumors of the mammary gland. After screening a battery of natural compounds similar to vincristine, voacamine was selected as a possible prolyl hydroxylase-2 activator, and its activity was evaluated using a 7,12-dimethylbenz[a]anthracene-induced rat model. The combination therapy was evaluated for cardiac toxicity using a hemodynamic profile. Angiogenic markers were evaluated by carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity using hematoxylin and eosin staining. The antioxidant potential was delineated using oxidative stress markers. The serum metabolomic profile was studied using NMR spectroscopy, and the disruption of fatty acids was evaluated using gas chromatography. Western blotting of proteins involved in hypoxic pathways was performed to decipher the action of therapy at the molecular level. Immunoblotting analysis validated that combination therapy has potential toss with prolyl hydroxylase-2 activity and thus initiates proteolytic degradation of hypoxia-inducible factor-1α and its consequent effects. Combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells. The present study explored the role of voacamine inactivation of prolyl hydroxylase-2, which can decrease the overexpression of hypoxia-inducible factor-1α and fatty acid synthase in mammary gland carcinoma cells.
format	article
author	Lakhveer Singh Subhadeep Roy Anurag Kumar Shubham Rastogi Dinesh Kumar Mohd. Nazam Ansari Abdulaziz S. Saeedan Manjari Singh Gaurav Kaithwas
author_facet	Lakhveer Singh Subhadeep Roy Anurag Kumar Shubham Rastogi Dinesh Kumar Mohd. Nazam Ansari Abdulaziz S. Saeedan Manjari Singh Gaurav Kaithwas
author_sort	Lakhveer Singh
title	Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia
title_short	Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia
title_full	Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia
title_fullStr	Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia
title_full_unstemmed	Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia
title_sort	repurposing combination therapy of voacamine with vincristine for downregulation of hypoxia-inducible factor-1α/fatty acid synthase co-axis and prolyl hydroxylase-2 activation in er+ mammary neoplasia
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/1b7ff98ce0c348bf9a53455e26809de0
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Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia

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