Abstract
Background Individual treatment with either the standard chemotherapeutic drug tamoxifen (Tam), the natural product hesperidin (Hes), or camel milk exosomes (Exo) has been shown to inhibit breast cancer MCF7 cells proliferation. However, little is known regarding their combined effect on MCF7 both in vitro and in vivo. Objective This study aimed to investigate whether the combined therapy of Tam, Hes, and Exo could synergistically inhibit the proliferation of MCF7 both in vitro and in vivo and could decrease Tam side effects. Results Combined treatment with Tam, Hes, and Exo significantly inhibited MCF7 proliferation as compared to the individual treatment. This cotreatment also had higher apoptotic, anti-migratory, and anti-invasive effects against MCF7 than individual treatment as revealed by; (1) Bax and caspase3 upregulation and Bcl2 downregulation; (2) downregulation of breast cancer-related genes (EGFR and ER alpha); (3) downregulation of MMP9 and upregulation of TIMP1; and (4) decreased number of migratory cells (transwell assay). This therapeutic potential was confirmed by the results of the in vivo study (mouse model of breast cancer induced by MCF7 xenograft). Cotreated mice had the smallest tumor size, highest Bax and caspase3, lowest Bcl2 and VEGF expression in the xenograft. This cotreatment was safer and reduced Tam side effects as revealed by; (1) lower serum levels of AST, ALT, creatinine, and urea; (2) lower levels of the lipid peroxide MDA; and (3) higher activities of the antioxidant enzymes CAT and GPx. Conclusion Cotreatment with tamoxifen, hesperidin, and camel milk exosomes synergistically inhibited MCF7 proliferation, migration and minimized tamoxifen adverse effects. Therefore, exosomes and hesperidin could be utilized as safe adjuvants/vehicles to tamoxifen during breast cancer chemotherapy.