Abstract
Simple SummaryOsteosarcoma 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.
Highlights
Osteosarcoma is the most common primary malignant tumor of the bone, mainly affecting children, teenagers, and young adults under the age of 20
We evaluated the plasma membrane fluidity and permeability of K7M2 murine osteosarcoma cells to increasing doses of simvastatin
−38% vs. solvent), and the combination of simvastatin to chemotherapy led to a stronger inhibitory effect than chemotherapy alone (+15% to +63% vs. drug alone). These results suggest that simvastatin reinforces the inhibitory effect of chemotherapy on tumor cells migration and invasion
Summary
Osteosarcoma is the most common primary malignant tumor of the bone, mainly affecting children, teenagers, and young adults under the age of 20. Adjuvant and neoadjuvant systemic chemotherapy regimens are considered the standard treatment for the past 40 years as they significantly improve the survival of patients [1]. Statins are widely used in clinical practice in the context of hypercholesterolemiaderived cardiovascular and coronary heart diseases [2]. These compounds inhibit the activity of the 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR) enzyme, the major rate-limiting enzyme in cholesterol neosynthesis [3]. In addition to the inhibition of cholesterol neosynthesis, those isoprenoid residues exert pleiotropic effects on several essential cellular functions, including cell proliferation, differentiation, and survival, and the regulation of cell morphology and motility
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