Abstract
SummaryBackground Statins inhibit the cholesterol biosynthesis and are used as cholesterol-lowering agents in fat-metabolism disorders. Furthermore, several studies state that statins have supportive functions in breast cancer treatment. Therefore, simvastatin (SVA) as a potential radiosensitizer should be investigated on the basis of human breast cells. Methods First, an optimal concentration of SVA for normal (MCF10A) and cancer (MCF-7) cells was identified via growth and cytotoxicity assays that, according to the definition of a radiosensitizer in the narrower sense, enhances the effect of radiation therapy but has no cytotoxic effect. Next, in combination with radiation SVA’s influence on DNA repair capacity and clonogenic survival in 2D and 3D was determined. Furthermore cell cycle distribution, expression of survivin and connective tissue growth factor (CTGF) as well as ERK1 map kinase were analysed. Results 1 μM SVA was identified as highest concentration without an influence on cell growth and cytotoxicity and was used for further analyses. In terms of early and residual γH2AX-foci, SVA affected the number of foci in both cell lines with or without irradiation. Different radiation responses were detected in 2D and 3D culture conditions. During the 2D cultivation, a radiosensitizing effect within the clonogenic survival was observable, but not in 3D. Conclusion The present study suggests that SVA may have potential for radiosensitization. Therefore, it is important to further investigate the role of SVA in relation to the extent of radiosensitization and how it could be used to positively influence the therapy of breast cancer or other entities.
Highlights
Simvastatin (SVA) belongs to the group of statins which act as competitive inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase and are used as cholesterollowering drugs
Investigation of cell growth and potential cytotoxicity after SVA treatment Only compounds are defined as radiosensitizer in a narrower sense, which increase the effect of radiotherapy but do not have a cytotoxic effect even in the administered concentration [26]
The first step was to find a concentration of SVA that is non-toxic to both cell lines and that could be used for all further experiments
Summary
Simvastatin (SVA) belongs to the group of statins which act as competitive inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-reductase and are used as cholesterollowering drugs. In this function, statins directly inhibit the formation of mevalonate from HMG-CoA and the biosynthesis of cholesterol [1]. Beckwitt et al (2018) have summarized the potential of statins to reduce the progression and mortality of breast cancer; they have supported the use of statins as a secondary prevention measure [8]. Within the scope of preoperative treatment with statins, a reduced tumour cell proliferation rate in breast cancer patient samples, Invest New Drugs (2021) 39:658–669 measured by the KI67-expression, was observed [9]. Not all tumour entities are sensitive to statins, there are studies that found no beneficial effect of them in a colon cancer cohort [11] and for triple negative breast cancer patients [12]
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