Therapeutic potential of mangiferin in cancer: Unveiling regulatory pathways, mechanisms of action, and bioavailability enhancements – An updated review

**Background:** Mangiferin (MGF) is a C-glycosylated xanthone (1,3,6,7-tetrahydroxyxanthone-C2-β-d-glucoside) primarily sourced from Mangifera indica (mango tree) and other medicinal plants. It possesses antioxidant, anti-inflammatory, and cytoprotective properties, with potential against diabetes, obesity, lung injuries, and cancer. Cancer remains a leading cause of mortality, responsible for 7 million deaths yearly. MGF has been studied against lung, liver, ovarian, prostate, breast, stomach, oral, colorectal, and other cancers. However, its clinical use is limited by low water solubility (0.111 mg/mL) and poor oral bioavailability.

**Methods:** This narrative review collected scientific literature from 2017–2022 using databases such as Google Scholar, Wiley, Scopus, and Science Direct, with keywords including 'mangiferin', 'cancer', and 'anticancer agent'. Studies included in vivo animal models (mice, rats, hamsters) and in vitro human cell lines. Various MGF formulations were examined: pure powder, liquid extracts, nanoparticles (gold-coated, silver-coated, phospholipid complexes), and combinations with chemotherapeutic drugs (cisplatin, doxorubicin). Bioavailability enhancement techniques included nanoprecipitation, solvent evaporation, nanostructured lipid carriers, supercritical antisolvent methods, and phospholipid complexation.

**Key Results:** MGF demonstrated antitumor effects across multiple cancer types. In colorectal cancer (CT26.WT cells in BALB/c mice), MGF at 100 mg/kg reduced tumor size by 75% and decreased intra-tumoral blood supply by 81% at 200 μg/mL. In prostate cancer, MGF-198AuNPs caused 85% reduction in tumor volume with >90% retention time. For oral cancer (DMBA-induced hamster model), MGF 50 mg/kg prevented tumor formation and normalized antioxidant enzyme levels. In ovarian cancer (OVCAR8 cells), MGF 25 μg/mL combined with cisplatin 1 μg/mL increased cisplatin sensitivity, decreased tumor cell motility, and improved survival. In leukemia (WEHI-3 cell line in mice), MGF 120 mg/kg increased body weight, decreased spleen and liver weights, and increased CD3 T-cells and CD19 B-cells while reducing CD11b monocytes and Mac-3 macrophages. In pancreatic cancer (Mia-PaCa2 cells), MGF inhibited growth at 10 μM (vs. 75 μM for normal cells), induced autophagy and apoptosis, and increased ROS at 20 μM. In breast cancer (MDA-MB231 cells), MGF suppressed PKM2 activity in a dose-dependent manner, with lowest activity at 360 μg/mL. In hepatocellular carcinoma (MHCC97L cells in mice), MGF 50 mg/kg inhibited tumor growth by downregulating LEF1 in the Wnt pathway. Bioavailability enhancements: MPLC-SNPs increased oral bioavailability 10-fold; MGF-NLC increased ophthalmic bioavailability 5.69-fold; MG-Na achieved 70% bioavailability; phospholipid complex increased bioavailability 9.75-fold; Carbopol 974P co-administration increased bioavailability 7-fold.

**Clinical Implications:** MGF shows promise as a multitargeted anticancer agent with low toxicity to normal cells, acting through modulation of signaling pathways (Wnt, PI3K/Akt, NFκB), immune responses (IL-6, IL-10, IL-12, TNF-α), and apoptotic proteins (Bcl-2, Bax, caspase-3). It can synergize with chemotherapeutic drugs like cisplatin and doxorubicin to overcome drug resistance. However, all evidence comes from preclinical studies (in vitro and animal models); no human trials are reported. Bioavailability enhancement strategies are critical for clinical translation. Further research is needed to establish effective doses, safety profiles, and efficacy in humans.