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

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.

Mechanisms of Epithelial-Mesenchymal Transition and Prevention of Dispase-Induced PVR by Delivery of an Antioxidant αB Crystallin Peptide

“…The effect of αBC-P on cell migration was evaluated using an in vitro scratch assay [ 39 , 40 ]. hRPE cells were incubated in a 3% FBS medium overnight.…”

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

“…The mechanistic action of MGF is supported by several evidence- and decrease in tumor migration (movement to other cells) (Katti et al, 2018;Rodriguez-Gonzalez et al, 2021;Tan et al, 2018). MGF causes downregulation of matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9), which result in decreased cellular proliferation (progression) and tumor motility; these processes ultimately lead to an increase in body weight (Zeng et al, 2020).…”

“…The first origin of MGF was Anemarrhena asphodeloides Bunge, which was greatly used in traditional Chinese medicine to treat neuropathy caused by diabetes (Jabeen et al., 2023; Lin et al., 2020). The major plant source of MGF is Mangifera indica (Family: Anacardiaceae ), commonly named as mango tree; fruit shells, stem, greenery, bark, roots, and seed (Aboyewa et al., 2021; Liu et al., 2021; Rodriguez‐Gonzalez et al., 2021; Yadav et al., 2022) and also found in a few other medicinal herbs and families like Salacia Chinensis ( roots ) (Zeng et al., 2020), Swertia chirata , Hypericum aucheri , Cyclopia intermedia (Aboyewa et al., 2021; Rodriguez‐Gonzalez et al., 2021), Anacardiaceae , Celastraceae , Gentianaceae families (Zeng et al., 2020), Zingiberaceae , Aphloiaceae Cnidii Rhizoma , Angelica Sinensis , and Levisticum officinale (Grauzdytė et al., 2019) an Aquilaria crassna (agarwood) (Thitikornpong et al., 2019) and honeybush tea (Chen et al., 2022; Zhang & Wang, 2018).…”

Mitochondrial Sirtuins in Chronic Degenerative Diseases: New Metabolic Targets in Colorectal Cancer

“…Among epi-nutrients , ergothioneine and δ-valerobetaine modulate SIRT3 and SIRT6 and oppose cancer viability and progression [ 76 , 118 , 119 , 120 ]. In addition, mangiferin and resveratrol show in vitro anticancer properties in CRC via SIRT/MGF and SIRT1/NF-κB signaling, respectively [ 135 , 150 , 151 ]. These are just some of the effects of epi-nutrients, extensively described in recent excellent reviews [ 152 , 153 , 154 ], showing the potential of mitochondrial SIRTs in the control of the development and progression of CRC.…”