Flavonoids in Cancer Metastasis

Abstract

Metastasis represents a serious complication in the treatment of cancer. Flavonoids are plant secondary metabolites exerting various health beneficiary effects. The effects of flavonoids against cancer are associated not only with early stages of the cancer process, but also with cancer progression and spread into distant sites. Flavonoids showed potent anti-cancer effects against various cancer models in vitro and in vivo, mediated via regulation of key signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of epithelial-mesenchymal transition or regulatory molecules such as MMPs, uPA/uPAR, TGF-β and other contributors of the complex process of metastatic spread. Moreover, flavonoids modulated also the expression of genes associated with the progression of cancer and improved inflammatory status, a part of the complex process involved in the development of metastasis. Flavonoids also documented clear potential to improve the anti-cancer effectiveness of conventional chemotherapeutic agents. Most importantly, flavonoids represent environmentally-friendly and cost-effective substances; moreover, a wide spectrum of different flavonoids demonstrated safety and minimal side effects during long-termed administration. In addition, the bioavailability of flavonoids can be improved by their conjugation with metal ions or structural modifications by radiation. In conclusion, anti-cancer effects of flavonoids, targeting all phases of carcinogenesis including metastatic progression, should be implemented into clinical cancer research in order to strengthen their potential use in the future targeted prevention and therapy of cancer in high-risk individuals or patients with aggressive cancer disease with metastatic potential.

Resveratrol Modulates Transforming Growth Factor-Beta (TGF-β) Signaling Pathway for Disease Therapy: A New Insight into Its Pharmacological Activities

“…Currently, extensive research is being performed for possible applications of natural products for the therapy of chronic diseases, as these agents can regulate multiple molecular targets and transcription factors [ 226 , 227 , 228 , 229 , 230 , 231 , 232 , 233 ]. In the present review, a comprehensive discussion of possible impact of Res on the TGF-β signaling pathway, which is one of the important cascades involved in the regulation of biological mechanisms and the generation of pathological events, is provided.…”

Curcumin’s Beneficial Effects on Neuroblastoma: Mechanisms, Challenges, and Potential Solutions

“…Some of these compounds can support cancer prevention and therapy or overcome cancer drug resistance with few or no side effects. Flavonoids, for example, suppress cancer through modulation of extracellular matrix (ECM) proteins, inhibition of the epithelial–mesenchymal transition (EMT), and inhibition of cancer cell metabolism [ 13 , 14 ]. Plant phenolic acids and lichens upregulate apoptosis, inhibit proliferation and metastasis, and induce cell cycle arrest, while vanilloids such as capsaicin exert anticancer effects through the modulation of intracellular calcium signaling [ 15 , 16 , 17 ].…”

The Potential of Phytochemicals in Oral Cancer Prevention and Therapy: A Review of the Evidence

“…More than 8000 phenolic compounds from plants have been reported, and the half of phenolic compounds is flavonoids presenting as aglycone, glycosides, and methylated derivatives [167]. Flavonoids have several subgroups which include flavonols, flavones, flavanonols, flavanols, flavanones, anthocyanidins, chalcones, and isoflavones [5,168]. Non-flavonoids compounds include phenolic acids, tannins, coumarins, lignans, and stilbens [169].…”

“…Metastasis represents a serious complication in cancer treatment. Studies have shown flavonoids have anti-cancer effects by regulating key signaling pathways involved in critical steps of metastatic spread in several in vitro and in vivo models [ 5 , 182 ]. Epigenetic changes could occur in the early stages of carcinogenesis preceding genetic mutations, so epigenetics are considered to be promising targets for early interventions against cancer using epigenetic biologically active substances [ 3 ].…”

“…Phytochemicals are natural biologically active compounds with potential health benefits; they have become a focus in recent years. Phytochemicals have been demonstrated to have anticancer effects, mainly by regulating epigenetics/epigenomics [ 3 ]; targeting cancer stem cells (CSCs) [ 4 ]; inhibiting cancer metastasis [ 5 ]; improving human immunity, antioxidation activity and anti-inflammatory responses [ 6 ]; inhibiting cancer cell cycle progression [ 7 ]; inhibiting cell signal transduction [ 8 ]; promoting cancer cell apoptosis [ 7 ]; and eventually, achieve the effect of inhibiting cancer cell proliferation and angiogenesis [ 9 , 10 , 11 ]. Several key mechanisms have been explored in leading to cell cycle arrest, proliferation inhibition, and apoptosis induction, such as down-regulation of cell cycle regulators cyclins [ 12 , 13 , 14 ] and cyclin dependent kinases [ 12 ], PI3K/Akt/mTOR and Erk signaling [ 15 ], anti-apoptotic proteins Bcl-2 and Bcl-xL [ 13 ], as well as enhancing tumor suppressor p21 [ 12 , 13 ] and p53 [ 13 ], pro-apoptotic proteins Bax, caspases and poly (ADP-ribose) polymerase (PARP) [ 13 , 14 ].…”