Preclinical activity of fluvastatin‐loaded self‐nanoemulsifying delivery system against breast cancer models: Emphasis on apoptosis

Abstract

Statins trigger apoptotic cell death in some types of growing tumor cells in a cholesterol‐lowering‐independent manner. Self‐nanoemulsifying delivery sys- tems (SNEDs) are potentially effective for the suppression of breast cancer development. This study aims to investigate the potential anticancer activity of fluvastatin (FLV)‐SNEDs in breast cancer while comparing it with FLV in vitro as well as in vivo exploiting/using MDA‐MB‐231 and Erhlich ascites carcinoma (EAC)‐bearing mice, respectively. Biochemical analysis of liver and kidney functions, oxidative stress markers, and histopathological examinations of such tumor tissues were performed showing the potentiality of SNEDs as a nanocarrier for antitumor agents. FLV‐SNEDs demonstrated more potent anticancer activity compared to FLV on MDA‐MB‐231 and hepatocellular carcinoma (HepG2) cells. In vivo experiments on the EAC‐ bearing mice model indicated that FLV and—to a greater extent—FLV‐SNEDs ameliorated EAC‐induced hepatotoxicity and nephrotoxicity. FLV or FLV‐ SNEDs evidently reduced the percent of Ki‐67 +ve EAC cells by 57.5% and 86.5% in comparison to the vehicle‐treated EAC group. In addition, FLV or FLV‐SNEDs decreased Bcl‐2 levels in serum and liver specimens. In contrast, FLV or FLV‐SNEDs significantly activated the executioner caspase‐3. Simultaneously, both FLV and FLV‐SNEDs stimulated p53 signaling and modulated Bcl‐2 protein levels in treated cells. Collectively, these results support the contribution of apoptotic cell death in mediating the anticancer activities of FLV and FLV‐SNEDs against murine EAC model in vivo. This study provides new understandings of how FLV and FLV‐SNEDs regulate EAC cell viability via upregulation of p53 signaling, and through modulation of cleaved caspase‐3 as well as antiapoptotic Bcl‐2 marker.