Abstract
Statins, including simvastatin (SMV), are commonly used for the control of hyperlipidaemia and have also proven therapeutic and preventative effects in cardiovascular diseases. Besides that, there is an emerging interest in their use as antineoplastic drugs as demonstrated by different studies showing their cytotoxic activity against different cancer cells. In this study, SMV-loaded emulsomes (SMV-EMLs) were formulated and evaluated for their cytotoxic activity in MCF-7 breast cancer cells. The emulsomes were prepared using a modified thin-film hydration technique. A Box–Behnken model was used to investigate the impact of formulation conditions on vesicle size and drug entrapment. The optimized formulation showed a spherical shape with a vesicle size of 112.42 ± 2.1 nm and an entrapment efficiency of 94.34 ± 1.11%. Assessment of cytotoxic activities indicated that the optimized SMV-EMLs formula exhibited significantly lower half maximal inhibitory concentration (IC50) against MCF-7 cells. Cell cycle analysis indicated the accumulation of cells in the G2-M phase as well as increased cell fraction in the pre-G1 phase, suggesting an enhancement of anti-apoptotic activity of SMV. The staining of cells with Annex V revealed an increase in early and late apoptosis, in line with the increased cellular content of caspase-3 and Bax. In addition, the mitochondrial membrane potential (MMP) was significantly decreased. In conclusion, SMV-EMLs demonstrated superior cell death-inducing activity against MCF-7 cells compared to pure SMV. This is mediated, at least in part, by enhanced pro-apoptotic activity and MMP modulation of SMV.
Highlights
Breast cancer is the most common type of cancer in women, which is frequently detected as an abnormal lump in the breast tissue [1,2]
Fitting to the selected models was based on the highest R2 and the lowest predicted residual error sum of squares (PRESS) (Table 3)
The present study clearly shows the enhanced cytotoxic activity exerted by the optimized SMV-EMLs formula on the well-characterized MCF-7 cancer cell model [21,27,28,29,30,31,53] compared with SMV alone
Summary
Breast cancer is the most common type of cancer in women, which is frequently detected as an abnormal lump in the breast tissue [1,2]. Treatment modalities of breast cancer are immunotherapy, chemotherapy, radiotherapy, hormonal therapy, targeted therapy, and surgery [3,4,5] Many of these treatments could lead to undesirable side effects due to high toxicity and long treatment process. Various scientific research and clinical trials demonstrated the potential of statins in the treatment of breast cancer [9] These studies demonstrated that statins have the ability to enhance apoptosis and radiosensitivity of breast cancer cells [10,11,12]. With regard to cell transport, in general, the transport of the statins, to which SMV belongs, is a competitive process between passive facilitated diffusion and active transport (e.g., pinocytosis) [16]. The more lipid-soluble the statin, the more it crosses cell membranes, and gains access to hepatic and non-hepatic cells through passive diffusion [18]
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