Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

Iara F Kretzer,1,2 Durvanei A Maria,3 Maria C Guido,1 Thaís C Contente,1 Raul C Maranhão1,2 1Laboratory of Metabolism and Lipids, Heart Institute of the Medical School Hospital, 2Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, University of São...

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Autores principales:	Kretzer IF, Maria DA, Guido MC, Contente TC, Maranhão RC
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2016
Materias:	lipid nanoparticles drug delivery statins cancer treatment melanoma. Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/533f7840b9794998a2abdb5a3e31abcc
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spelling	oai:doaj.org-article:533f7840b9794998a2abdb5a3e31abcc2021-12-02T02:01:52ZSimvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice1178-2013https://doaj.org/article/533f7840b9794998a2abdb5a3e31abcc2016-03-01T00:00:00Zhttps://www.dovepress.com/simvastatin-increases-the-antineoplastic-actions-of-paclitaxel-carried-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Iara F Kretzer,1,2 Durvanei A Maria,3 Maria C Guido,1 Thaís C Contente,1 Raul C Maranhão1,2 1Laboratory of Metabolism and Lipids, Heart Institute of the Medical School Hospital, 2Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, University of São Paulo, 3Biochemistry and Biophysics Laboratories, Butantan Institute, São Paulo, Brazil Purpose: Lipid nanoemulsions (LDEs) that bind to low-density lipoprotein (LDL) receptors used as carriers of paclitaxel (PTX) can decrease toxicity and increase PTX antitumoral action. The administration of simvastatin (Simva), which lowers LDL-cholesterol, was tested as an adjuvant to commercial PTX and to PTX associated with LDE (LDE-PTX). Materials and methods: B16F10 melanoma-bearing mice were treated with saline solution or LDE (controls), Simva, PTX, PTX and Simva, LDE-PTX, and LDE-PTX and Simva: PTX dose 17.5 µmol/kg (three intraperitoneal injections, 3 alternate days): Simva 50 mg/kg/day by gavage, 9 consecutive days. Results: Compared with saline controls, 95% tumor-growth inhibition was achieved by LDE-PTX and Simva, 61% by LDE-PTX, 44% by PTX and Simva, and 43% by PTX. Simva alone had no effect. Metastasis developed in only 37% of the LDE-PTX and Simva, 60% in LDE-PTX, and 90% in PTX and Simva groups. Survival rates were higher in LDE-PTX and Simva and in LDE-PTX groups. The LDE-PTX and Simva group presented tumors with reduced cellular density and increased collagen fibers I and III. Tumors from all groups showed reduction in immunohistochemical expression of ICAM, MCP-1, and MMP-9; LDE-PTX and Simva presented the lowest MMP-9 expression. Expression of p21 was increased in the Simva, LDE-PTX, and LDE-PTX and Simva groups. In the Simva and LDE-PTX and Simva groups, expression of cyclin D1, a proliferation and survival promoter of tumor cells, was decreased. Therapy with LDE-PTX and Simva showed negligible toxicity compared with PTX and Simva, which resulted in weight loss and myelosuppression. Conclusion: Simva increased the antitumor activity of PTX carried in LDE but not of PTX commercial presentation, possibly because statins increase the expression of LDL receptors that internalize LDE-PTX. Keywords: lipid nanoparticles, drug delivery, statins, cancer treatment, B16F10 melanomaKretzer IFMaria DAGuido MCContente TCMaranhão RCDove Medical Pressarticlelipid nanoparticlesdrug deliverystatinscancer treatmentmelanoma.Medicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2016, Iss Issue 1, Pp 885-904 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	lipid nanoparticles drug delivery statins cancer treatment melanoma. Medicine (General) R5-920
spellingShingle	lipid nanoparticles drug delivery statins cancer treatment melanoma. Medicine (General) R5-920 Kretzer IF Maria DA Guido MC Contente TC Maranhão RC Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice
description	Iara F Kretzer,1,2 Durvanei A Maria,3 Maria C Guido,1 Thaís C Contente,1 Raul C Maranhão1,2 1Laboratory of Metabolism and Lipids, Heart Institute of the Medical School Hospital, 2Department of Clinical Chemistry, Faculty of Pharmaceutical Sciences, University of São Paulo, 3Biochemistry and Biophysics Laboratories, Butantan Institute, São Paulo, Brazil Purpose: Lipid nanoemulsions (LDEs) that bind to low-density lipoprotein (LDL) receptors used as carriers of paclitaxel (PTX) can decrease toxicity and increase PTX antitumoral action. The administration of simvastatin (Simva), which lowers LDL-cholesterol, was tested as an adjuvant to commercial PTX and to PTX associated with LDE (LDE-PTX). Materials and methods: B16F10 melanoma-bearing mice were treated with saline solution or LDE (controls), Simva, PTX, PTX and Simva, LDE-PTX, and LDE-PTX and Simva: PTX dose 17.5 µmol/kg (three intraperitoneal injections, 3 alternate days): Simva 50 mg/kg/day by gavage, 9 consecutive days. Results: Compared with saline controls, 95% tumor-growth inhibition was achieved by LDE-PTX and Simva, 61% by LDE-PTX, 44% by PTX and Simva, and 43% by PTX. Simva alone had no effect. Metastasis developed in only 37% of the LDE-PTX and Simva, 60% in LDE-PTX, and 90% in PTX and Simva groups. Survival rates were higher in LDE-PTX and Simva and in LDE-PTX groups. The LDE-PTX and Simva group presented tumors with reduced cellular density and increased collagen fibers I and III. Tumors from all groups showed reduction in immunohistochemical expression of ICAM, MCP-1, and MMP-9; LDE-PTX and Simva presented the lowest MMP-9 expression. Expression of p21 was increased in the Simva, LDE-PTX, and LDE-PTX and Simva groups. In the Simva and LDE-PTX and Simva groups, expression of cyclin D1, a proliferation and survival promoter of tumor cells, was decreased. Therapy with LDE-PTX and Simva showed negligible toxicity compared with PTX and Simva, which resulted in weight loss and myelosuppression. Conclusion: Simva increased the antitumor activity of PTX carried in LDE but not of PTX commercial presentation, possibly because statins increase the expression of LDL receptors that internalize LDE-PTX. Keywords: lipid nanoparticles, drug delivery, statins, cancer treatment, B16F10 melanoma
format	article
author	Kretzer IF Maria DA Guido MC Contente TC Maranhão RC
author_facet	Kretzer IF Maria DA Guido MC Contente TC Maranhão RC
author_sort	Kretzer IF
title	Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice
title_short	Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice
title_full	Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice
title_fullStr	Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice
title_full_unstemmed	Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice
title_sort	simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice
publisher	Dove Medical Press
publishDate	2016
url	https://doaj.org/article/533f7840b9794998a2abdb5a3e31abcc
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Simvastatin increases the antineoplastic actions of paclitaxel carried in lipid nanoemulsions in melanoma-bearing mice

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