Role of Novel Nutraceuticals Garcinol, Plumbagin and Mangiferin in the Prevention and Therapy of Human Malignancies: Mechanisms of Anticancer Activity

Abstract

Nutraceuticals from natural sources have been investigated for their putative chemopreventive and cancer therapeutic properties for the last few decades. The interest in these compounds is in part due to their pleiotropic effects and relatively non-toxic nature. A large number of such nutraceuticals are under detailed investigations worldwide but most of them suffer from the lack of sufficient bioavailability in humans. The identification and characterization of novel natural compounds with sufficient anticancer potential is therefore an ongoing process. This article is a summary of anticancer activity of three such novel nutraceuticals, namely garcinol, plumbagin and mangiferin. These compounds have shown promising biological activity in preliminary studies by targeting multiple signaling pathways. In particular, it seems that the inhibition of NF-κB pathway is one of the major mechanism through which these compounds exhibit their anticancer and apoptosis-inducing effects. The data on their anticancer activity is just emerging and the information on their bioavailability is still insufficient to predict their future application in the clinical settings. In this article, we have surveyed the available literature to summarize the mechanisms of anticancer activity of these three novel nutraceuticals. We also discuss the challenges and possible solutions to realize the dream on the translational potential of these compounds into clinical practice for the prevention and/or treatment of human malignancies.

Mangiferin and Cancer: Mechanisms of Action

“…In its phosphorylated form, IRAK1 interacts with Tumour necrosis factor Receptor-Associated Factor 6 (TRAF6) to form a complex, which signals sequentially through Transforming growth factor beta-activated kinase 1/Transforming growth factor beta-activated kinase 1-binding protein 1 and 2 (TAK1/TAB1/TAB2), NFκB Essential Modulator/Inhibitor of NF B Kinase subunit-β/Inhibitor of NF B Kinase subunit-α (NEMO/IKK-β/IKK-α) and Inhibitor of κB (IκB)/p50/p65 complexes to ultimately activate NFκB [ 57 ]. Recent findings suggest mangiferin inhibits NFκB activation at various steps in the pathway ( Figure 2 A,B) [ 11 , 47 ]. NFκB can be activated via the classical or alternative pathways.…”

“…This is of particular relevance to LDCs, where the more expensive chemotherapeutic drugs may be inaccessible, while mangiferin containing plants are abundant. In MDCs, the potential enhanced synergistic effect seen with major chemotherapeutic drugs may allow for lower dosages of drugs, thus reducing toxicity and providing greater selective toxicity to malignant cells, reducing the extent of side effects [ 47 ]. However, it is acknowledged that the quantity of fruit required in order to achieve clinically relevant levels of mangiferin may be unreasonably high.…”

Garcinol Regulates EMT and Wnt Signaling PathwaysIn VitroandIn Vivo, Leading to Anticancer Activity against Breast Cancer Cells

“…1A) is a polyisoprenylated benzophenone derivative that is obtained from Garcinia indica extracts (3). Early studies with garcinol focused on its antioxidant abilities (3–5), but gradually its potent anticancer activity was recognized as well (5–16). Despite the increasing interest in anticancer activity of garcinol, the exact molecular mechanism of its action is not yet known.…”

“…Because the process of EMT itself involves the crucial role of NF-κB signaling in breast cancer cells (21), we questioned whether the mechanism of action of garcinol could involve the regulation of novel miRNAs and the resulting EMT to MET (mesenchymal-to-epithelial transition) through NF-κB signaling. Also, there is evidence to suggest the influence of nutraceuticals on multiple signaling pathways, including the Wnt signaling pathway (22), and that garcinol being a nutraceutical itself (16), it may regulate the Wnt signaling cross-talk with NF-κB signaling (23). Therefore, this study was designed to assess the effect of garcinol on Wnt signaling pathway and further assessed the mechanistic involvement of novel miRNAs, EMT, and NF-κB in the regulation of Wnt signaling.…”

The potential role of mangiferin in cancer treatment through its immunomodulatory, anti‐angiogenic, apoptopic, and gene regulatory effects

“…Neither single strand breaks nor alkali-labile sites in blood peripheral lymphocytes or hepatocytes were observed after 1 h exposition to 10-500 lg/mL of MF under the Comet assay. Furthermore, micronucleus studies showed that MF neither induced cytotoxic activity nor increased the frequency of micronucleated/binucleated cells in mice bone marrow; and protected cells against DNA damage [93].…”