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 anticancer drugs. We demonstrate that CRC treatment with the phytopharmaceutical
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 immunocompetent allograft mouse model of murine CT26 colon
carcinoma, which increases overall survival of mice. Antimetastatic and antiangiogenic MGF effects could be further validated in a wound healing in vitro model in human HT29 cells and in a
matrigel plug implant mouse model. Interestingly, transcriptome pathway enrichment analysis demonstrates that MGF inhibits
tumor growth,
metastasis and angiogenesis by multi-targeting of mitochondrial
oxidoreductase and
fatty acid β-oxidation metabolism,
PPAR,
SIRT, NFκB, Stat3, HIF, Wnt and GP6 signaling pathways. MGF effects on
fatty acid β-oxidation metabolism and
carnitine palmitoyltransferase 1 (CPT1)
protein expression could be further confirmed in vitro in human HT29 colon cells. In conclusion, antitumor, antiangiogenic and antimetastatic effects of MGF treatment hold promise to reduce adverse toxicity and to mitigate therapeutic outcome of
colorectal cancer treatment by targeting mitochondrial energy metabolism in the tumor microenvironment.