Mangiferin induced fatty acid b-oxidation and ketogenic metabolism promote antiproliferative, antiangiogenic and antimetastatic therapeutic effects in a preclinical colorectal cancer mouse model

In spite of the current advances and achievements in cancer treatments, colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. Drug resistance, adverse side effects and high rate of angiogenesis, metastasis and tumor relapse remain one of the greatest challenges in long-term management of CRC and urges need for new leads of anti-cancer drugs. Plant-derived natural products have historically been a major source of novel anti-cancer phytopharmaceuticals. We demonstrate that CRC treatment with mangiferin (MGF), a glucosylxanthone present in Mango tree stem bark and leaves (Mangifera Indica L.), induces dose-dependent tumor regression and decreases lung metastasis in a syngeneic subcutaneous allograft mouse model with CT26 colon cancer cells, which increases overall survival of mice. MGF treatment also elicits antiangiogenic effects in the matrigel plug implant mouse model. Interestingly, transcriptome and pathway enrichment analysis demonstrates that MGF induced fatty acid b-oxidation generates ketogenic metabolism which inhibits tumor growth, metastasis and angiogenesis by multi-targeting of PPAR, NFκB, Stat3, HIF, HDAC/SIRT, Wnt and GP6 signaling pathways. In conclusion, MGF holds promise as a novel class of ketogenic diet mimetic phytopharmaceutical compounds which promote therapeutic antitumor, antiangiogenic and antimetastatic effects in a preclinical colorectal cancer mouse model.This work has been supported by projects ZEIN2011PR383, ZEIN2016PR418 and ZEIN2016PR420 (Flemish VLIR collaboration program), Belgiu