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Article

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

1
Inserm, UMR981, Gustave Roussy Cancer Campus, Paris-Saclay University, F-94805 Villejuif, France
2
Ecole Nationale Supérieure de Chimie de Montpellier, F-34090 Montpellier, France
3
Inserm, U1015, Gustave Roussy Cancer Campus, Paris-Saclay University, F-94805 Villejuif, France
4
Child and Adolescent Cancer Department, Gustave Roussy Cancer Campus, F-94805 Villejuif, France
*
Author to whom correspondence should be addressed.
Academic Editor: Maria Smolle
Cancers 2021, 13(22), 5869; https://doi.org/10.3390/cancers13225869
Received: 20 October 2021 / Revised: 13 November 2021 / Accepted: 19 November 2021 / Published: 22 November 2021
Osteosarcoma is the most common form of primary solid bone malignancy, with the highest incidence in adolescence. The therapeutic management includes surgical resection combined with adjuvant/neoadjuvant chemotherapy regimens. Despite this multimodal combination, about two patients out of five are still not cured (5-year overall survival rate at 60%). Complementary therapeutic approaches are required to overcome the frequent resistance to conventional chemotherapy. The aim of the present study was to assess the potential benefit of statins as an adjuvant to chemotherapy. We show that simvastatin synergizes with conventional chemotherapy drugs in terms of cell viability, tumor growth, and dissemination and represents valuable alternative adjuvant therapy that needs further investigation in clinical trials.
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%, p < 0.05) and metastatic spread (+50%, p < 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. View Full-Text
Keywords: chemoresistance; adjuvant therapy; bone tumor; invasion; mevalonate pathway; statin chemoresistance; adjuvant therapy; bone tumor; invasion; mevalonate pathway; statin
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MDPI and ACS Style

Mangelinck, A.; Habel, N.; Mohr, A.; Gaspar, N.; Stefanovska, B.; Fromigué, O. Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma. Cancers 2021, 13, 5869. https://doi.org/10.3390/cancers13225869

AMA Style

Mangelinck A, Habel N, Mohr A, Gaspar N, Stefanovska B, Fromigué O. Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma. Cancers. 2021; 13(22):5869. https://doi.org/10.3390/cancers13225869

Chicago/Turabian Style

Mangelinck, Adèle, Nadia Habel, Audrey Mohr, Nathalie Gaspar, Bojana Stefanovska, and Olivia Fromigué. 2021. "Synergistic Anti-Tumor Effect of Simvastatin Combined to Chemotherapy in Osteosarcoma" Cancers 13, no. 22: 5869. https://doi.org/10.3390/cancers13225869

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