Diet-derived Flavonoids: Bridging Epidemiological Chemoprevention and Preclinical Anti-tumor Mechanisms in Clinical Oncology

Flavonoids are an abundantly consumed group of dietary polyphenols present in fruits, vegetables, teas, herbs and other plant-derived foods composed of a diphenylpropane (C6-C3-C6) ring structure, allowing subclassification into flavonols, flavones, flavan-3-ols, anthocyanins and isoflavones based on substitutions on the heterocyclic C ring. Multiple case-control studies and prospective cohort analyses reveal higher intake of certain flavonoid subgroups associated with reduced risk of various epithelial cancers like lung, breast, pancreatic, oral and liver. In vitro studies across diverse human cancer cell lines and in vivo, animal models demonstrate anticancer effects of select flavonoids either directly or in synergy with chemotherapy by targeting hallmark capabilities that enable tumours including resisting cell death, sustaining proliferation, inducing angiogenesis, activating invasion and metastasis. The well-explored anticancer mechanisms range from direct antioxidant activity, quenching free radicals and bolstering endogenous defenses; to anti-inflammatory signalling via NF-κB and cytokine modulation; epigenetic alterations by chromatin remodeling; to direct regulation of cell cycle controllers (CDKs, cyclins) and apoptotic mediators (caspases, Bcl-2. Early human trials mostly indicate the safe use of certain flavonoids and subclasses at tested doses however, progression to therapeutic benefit faces challenges like suboptimal systemic availability upon metabolism, unclear metabolite activities and study design limitations regarding delivery methods, combination treatments and clinical priority. In essence, dietary flavonoids exhibit pleiotropic pharmacological strengths against cancer progression warranting expanded translational research and human trials to develop formulations/delivery systems and validate targeted clinical integration, especially alongside chemotherapy regimens.