Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma

Context: Osteosarcoma is the most common primary solid malignancy of the bone, mainly affecting pediatric patients. The main clinical issues are chemoresistance and metastatic spread, leading to a survival rate stagnating around 60% for four decades. Purpose: Here, we investigated the effect of simv...

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Autores principales:	Adèle Mangelinck, Nadia Habel, Audrey Mohr, Nathalie Gaspar, Bojana Stefanovska, Olivia Fromigué
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chemoresistance adjuvant therapy bone tumor invasion mevalonate pathway statin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/a4b48723a9fb48919cb3617c384370ae
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spelling	oai:doaj.org-article:a4b48723a9fb48919cb3617c384370ae2021-11-25T17:04:56ZSynergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma10.3390/cancers132258692072-6694https://doaj.org/article/a4b48723a9fb48919cb3617c384370ae2021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/22/5869https://doaj.org/toc/2072-6694Context: Osteosarcoma is the most common primary solid malignancy of the bone, mainly affecting pediatric patients. The main clinical issues are chemoresistance and metastatic spread, leading to a survival rate stagnating around 60% for four decades. Purpose: Here, we investigated the effect of simvastatin as adjuvant therapy on chemotherapy. Methods: Cell viability was assessed by the MTT test, and a combination index was evaluated by an isobologram approach. Cell motility was assessed by wound-healing assay. Cell-derived xenograft models were established in mice. FFPE tumor samples were assessed by immunohistochemistry. Results: In vitro experiments indicate that simvastatin synergized the conventional chemotherapy drugs’ inhibitory effect on cell viability. Functional assays reveal that simvastatin supplementation favored the anticancer mechanism of action of the tested chemotherapy drugs, such as DNA damage through intercalation or direct alkylation and disorganization of microtubules. Additionally, we show that even though simvastatin alone did not modify tumor behavior, it potentiated the inhibitory effect of doxorubicin on primary tumor growth (+50%, <i>p</i> < 0.05) and metastatic spread (+50%, <i>p</i> < 0.05). Our results provide evidence that simvastatin exerted an anti-tumor effect combined with chemotherapy in the preclinical murine model and represents valuable alternative adjuvant therapy that needs further investigation in clinical trials.Adèle MangelinckNadia HabelAudrey MohrNathalie GasparBojana StefanovskaOlivia FromiguéMDPI AGarticlechemoresistanceadjuvant therapybone tumorinvasionmevalonate pathwaystatinNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5869, p 5869 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chemoresistance adjuvant therapy bone tumor invasion mevalonate pathway statin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	chemoresistance adjuvant therapy bone tumor invasion mevalonate pathway statin Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Adèle Mangelinck Nadia Habel Audrey Mohr Nathalie Gaspar Bojana Stefanovska Olivia Fromigué Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma
description	Context: Osteosarcoma is the most common primary solid malignancy of the bone, mainly affecting pediatric patients. The main clinical issues are chemoresistance and metastatic spread, leading to a survival rate stagnating around 60% for four decades. Purpose: Here, we investigated the effect of simvastatin as adjuvant therapy on chemotherapy. Methods: Cell viability was assessed by the MTT test, and a combination index was evaluated by an isobologram approach. Cell motility was assessed by wound-healing assay. Cell-derived xenograft models were established in mice. FFPE tumor samples were assessed by immunohistochemistry. Results: In vitro experiments indicate that simvastatin synergized the conventional chemotherapy drugs’ inhibitory effect on cell viability. Functional assays reveal that simvastatin supplementation favored the anticancer mechanism of action of the tested chemotherapy drugs, such as DNA damage through intercalation or direct alkylation and disorganization of microtubules. Additionally, we show that even though simvastatin alone did not modify tumor behavior, it potentiated the inhibitory effect of doxorubicin on primary tumor growth (+50%, <i>p</i> < 0.05) and metastatic spread (+50%, <i>p</i> < 0.05). Our results provide evidence that simvastatin exerted an anti-tumor effect combined with chemotherapy in the preclinical murine model and represents valuable alternative adjuvant therapy that needs further investigation in clinical trials.
format	article
author	Adèle Mangelinck Nadia Habel Audrey Mohr Nathalie Gaspar Bojana Stefanovska Olivia Fromigué
author_facet	Adèle Mangelinck Nadia Habel Audrey Mohr Nathalie Gaspar Bojana Stefanovska Olivia Fromigué
author_sort	Adèle Mangelinck
title	Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma
title_short	Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma
title_full	Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma
title_fullStr	Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma
title_full_unstemmed	Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma
title_sort	synergistic anti-tumor effect of simvastatin combined to chemotherapy in osteosarcoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a4b48723a9fb48919cb3617c384370ae
work_keys_str_mv	AT adelemangelinck synergisticantitumoreffectofsimvastatincombinedtochemotherapyinosteosarcoma AT nadiahabel synergisticantitumoreffectofsimvastatincombinedtochemotherapyinosteosarcoma AT audreymohr synergisticantitumoreffectofsimvastatincombinedtochemotherapyinosteosarcoma AT nathaliegaspar synergisticantitumoreffectofsimvastatincombinedtochemotherapyinosteosarcoma AT bojanastefanovska synergisticantitumoreffectofsimvastatincombinedtochemotherapyinosteosarcoma AT oliviafromigue synergisticantitumoreffectofsimvastatincombinedtochemotherapyinosteosarcoma
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Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma

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