Citrus sinensis (L) peels extract inhibits metastasis of breast cancer cells by targeting the downregulation matrix metalloproteinases-9

Abstract

BACKGROUND: Long-term use of doxorubicin (DOX) chemotherapy causes several side effects, especially induction of metastasis on breast cancer (BC). There is an urgent need to identify novel agent with low side effect targeting BC metastasis. Citrus sinensis (L.) peels extract (CSP) has long been used for the treatment of several cancers. However, its anti-metastatic potential against BC metastatic remains unclear. AIM: This study aimed to explore the role of CSP in combination with DOX in inhibiting the migration of metastatic BC MDA-MB-231 cells. MATERIALS AND METHODS: Potential cytotoxic in single and combination was analyzed 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay [MTT] assay). The anti-metastatic activities of several major compounds on CSP including hesperetin, tangeretin, nobiletin, naringenin, and hesperidin were screened by molecular docking under protein-ligand ant system software. RESULTS: Based on molecular docking, we revealed that the selected protein target matrix metalloproteinases-9 (PBD ID:2OVX) has lower docking score for hesperetin, tangeretin, nobiletin, naringenin, and hesperidin compare to DOX. CSP and DOX individually exhibited strong cytotoxic effect on MDA-MB-231 cells under MTT assay with IC50 value of 344 µg/mL and 85 nM, respectively. Furthermore, CSP in combination with DOX synergistically increased the cytotoxicity of DOX. Here, we showed that CSP can specifically suppress the side effect of DOX-induced metastasis by reduces doses of DOX. However, low doses of DOX in combination with CSP still potential inhibited cancer cells growth. CONCLUSION: CSP increased the cytotoxicity and inhibited the induction of metastasis by DOX in BC cells so that CSP potential to be developed as co-chemotherapeutic agent.