Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression

Abstract Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to the development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated b...

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Main Authors: Valentin-Florian Rauca, Laura Patras, Lavinia Luput, Emilia Licarete, Vlad-Alexandru Toma, Alina Porfire, Augustin Catalin Mot, Elena Rakosy-Tican, Alina Sesarman, Manuela Banciu
Format: Article
Language:English
Published: Nature Portfolio 2021-11-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-021-01284-5
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author Valentin-Florian Rauca
Laura Patras
Lavinia Luput
Emilia Licarete
Vlad-Alexandru Toma
Alina Porfire
Augustin Catalin Mot
Elena Rakosy-Tican
Alina Sesarman
Manuela Banciu
author_facet Valentin-Florian Rauca
Laura Patras
Lavinia Luput
Emilia Licarete
Vlad-Alexandru Toma
Alina Porfire
Augustin Catalin Mot
Elena Rakosy-Tican
Alina Sesarman
Manuela Banciu
author_sort Valentin-Florian Rauca
collection DOAJ
description Abstract Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to the development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy almost totally inhibited (> 90%) the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and simultaneous induction of a pro-apoptotic state of tumor cells in the tumor microenvironment (TME). These effects were accompanied by the partial re-education of TAMs towards an M1 phenotype and augmented by combined therapy-induced suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the TME, by suppressing its most important malignant biological capabilities.
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spelling doaj.art-03c6b0e8b4f24848a334855428de8d782022-12-21T20:37:33ZengNature PortfolioScientific Reports2045-23222021-11-0111111510.1038/s41598-021-01284-5Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progressionValentin-Florian Rauca0Laura Patras1Lavinia Luput2Emilia Licarete3Vlad-Alexandru Toma4Alina Porfire5Augustin Catalin Mot6Elena Rakosy-Tican7Alina Sesarman8Manuela Banciu9Department of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai UniversityDepartment of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai UniversityDepartment of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai UniversityDepartment of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai UniversityDepartment of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai UniversityDepartment of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy “Iuliu Hatieganu”Research Center for Advanced Chemical Analysis, Instrumentation and Chemometrics, Faculty of Chemistry and Chemical Engineering, Babes-Bolyai UniversityDepartment of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai UniversityDepartment of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai UniversityDepartment of Molecular Biology and Biotechnology, and Center of Systems Biology, Biodiversity and Bioresources, Faculty of Biology and Geology, Babes-Bolyai UniversityAbstract Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to the development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy almost totally inhibited (> 90%) the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and simultaneous induction of a pro-apoptotic state of tumor cells in the tumor microenvironment (TME). These effects were accompanied by the partial re-education of TAMs towards an M1 phenotype and augmented by combined therapy-induced suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the TME, by suppressing its most important malignant biological capabilities.https://doi.org/10.1038/s41598-021-01284-5
spellingShingle Valentin-Florian Rauca
Laura Patras
Lavinia Luput
Emilia Licarete
Vlad-Alexandru Toma
Alina Porfire
Augustin Catalin Mot
Elena Rakosy-Tican
Alina Sesarman
Manuela Banciu
Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression
Scientific Reports
title Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression
title_full Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression
title_fullStr Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression
title_full_unstemmed Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression
title_short Remodeling tumor microenvironment by liposomal codelivery of DMXAA and simvastatin inhibits malignant melanoma progression
title_sort remodeling tumor microenvironment by liposomal codelivery of dmxaa and simvastatin inhibits malignant melanoma progression
url https://doi.org/10.1038/s41598-021-01284-5
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