Antiproliferative, Antiangiogenic, and Antimetastatic Therapy Response by Mangiferin in a Syngeneic Immunocompetent Colorectal Cancer Mouse Model Involves Changes in Mitochondrial Energy Metabolism.

Julio César Rodriguez-Gonzalez,Wim Vanden Berghe,Olga Luisa Quiñones-Maza,Idania Rodeiro-Guerra,Ivones Hernández-Balmaseda,Claudina Pérez-Novo,Geovanni Dantas-Cassali,Ken Declerck,Patrycja Jakubek,Miriam Teresa Lopes Paz,René Delgado-Hernández,Claudia Theys,Emilie Logie,Diego Carlos Dos Reis,Guy Van Camp

doi:10.3389/fphar.2021.670167

Abstract

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.

Highlights

The latest GLOBOCAN 2018 database showed that colorectal cancer (CRC) is placed third in incidence and second in mortality worldwide, respectively; being responsible for 10% of all newly diagnosed cancer cases, and 9% of all cancer deaths worldwide (Bray et al, 2018)
The culture medium RPMI-1640, dimethylsulfoxide (DMSO), fetal bovine serum, penicillin-streptomycin (100x), L-Glutamine, trypsin, ethylenediaminetetraacetic acid (EDTA), sodium dodecyl sulphate (SDS), reduced Matrigel (196 USP unit/ mg) and set of Drabkin reagents were purchased from Sigma-Aldrich Inc. (Saint Louis, MO, United States). 3-(4,5-Dimethyl-2-thiazolyl)2,5-diphenyl-2H-tetrazolium bromide (MTT), 2-propanol, ethanol, hydrochloric acid (HCl), formaldehyde and acetic acid were obtained from Merck KGaA (Germany)
The CT26 syngeneic colorectal cancer tumor model was used to investigate the effect of MGF on tumor growth in vivo

Summary

Introduction

The latest GLOBOCAN 2018 database showed that colorectal cancer (CRC) is placed third in incidence and second in mortality worldwide, respectively; being responsible for 10% of all newly diagnosed cancer cases, and 9% of all cancer deaths worldwide (Bray et al, 2018). The effectiveness of current chemotherapies is limited (Pritchard et al, 2012) due to suppression of host immune antitumor responses (Teng et al, 2015; Bhatia and Kumar, 2016), therapy-induced tumor resistance, tumor relapse (Shaked, 2016) local/systemic toxicities and increased risk of secondary tumorigenesis (Pritchard et al, 2012; Abdullah and Chow, 2013) In this scenario more than 80% of patients with mCRC die during the long-term follow-up (Ting et al, 2013). The number of phytochemical products submitted to the FDA is high in the oncological area

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