Regulation of cell migration, proliferation, and apoptosis through Psidium guajava extract against breast cancer: Cross-talk of AKT/FOXO3 and MAPK cascade and related miRNAs

Abstract

Breast cancer is a major health problem due to its growing prevalence and mortality, necessitating new, safer, and multi-targeted alternative therapies. Thus, the present study explored the phytochemical properties and anti-breast cancer potential of Psidium guajava L. methanolic extract (GuL). Briefly, the phytochemical analysis confirmed the presence of secondary metabolites, with HPLC revealing abundant flavonoids like kaempferol, myricetin, and quercetin. Antioxidant potential was also evaluated via DPPH and reducing power assays. Moreover, molecular docking identified quercetin (-9.7 Kcal/mol) and myricetin (-9.5 Kcal/mol) as potential inhibitors of AKT1, whereas, guavin (-9.1 Kcal/mol) and lletatifol (-9.0 Kcal/mol) as best hits for FOXO3 protein. In vitro experiments including MTT assay, mitochondrial membrane potential analysis, FACS-based cell cycle analysis, and wound healing assay exhibited cytotoxic, cytostatic, and anti-metastatic activities of GuL. Mechanistically, GuL modulated AKT/FOXO3 and MAPK pathway candidates. Real-time and western-blot analysis showed downregulation of IRS1, AKT, and RAF1 genes while modulating FOXO3 expression differently in the two cell lines. miRNA analysis via real-time PCR showed suppression of oncogenic miRNAs i.e., miRNA-18a, miRNA-182, and miRNA-190b. So, the findings indicate that guava leaf extract can be a potential source for developing safe and effective anti-breast cancer therapy.