Flavonoids as Modulators of the p53-Bcl-2 Axis in Cancer: Molecular Mechanisms and Therapeutic Implications

Cancer progression is closely associated with dysregulation of apoptosis, enabling malignant cells to evade programmed cell death and develop resistance to therapy. Among the key regulators of this process, the tumor suppressor protein p53 and the Bcl-2 family of proteins play central and interconnected roles in controlling cell survival and mitochondrial integrity. In recent years, naturally occurring flavonoids have attracted considerable attention as potential modulators of these pathways due to their diverse biological activities and relatively low toxicity. This review provides a focused and integrative overview of how different subclasses of flavonoids modulate the p53-Bcl-2 signaling axis to regulate apoptosis in cancer cells. Particular emphasis is placed on the mechanistic interplay between p53 stabilization, transcriptional regulation of apoptotic targets, mitochondrial outer membrane permeabilization, and caspase activation. In contrast to previous general reviews on flavonoids and cancer, this work provides an integrated overview of evidence across multiple flavonoid subclasses and experimental cancer models, highlighting both shared and pathway-specific apoptotic responses. Experimental findings from in vitro and in vivo studies are discussed, including the effects of quercetin, kaempferol, myricetin, epigallocatechin gallate, and related compounds on cell-cycle arrest, oxidative stress, mitochondrial dysfunction, and intrinsic apoptotic signaling. Furthermore, the review examines the relationship between flavonoid chemical structure and biological activity, with particular attention to bioavailability, metabolic transformation, and strategies aimed at improving therapeutic efficacy, including structural modification and nanocarrier-based delivery systems. Despite promising preclinical findings, significant translational challenges remain, including poor pharmacokinetic properties, variability among experimental models, and limited clinical validation. Overall, flavonoids represent a promising class of bioactive compounds capable of targeting apoptosis through modulation of the p53-Bcl-2 network, and a deeper mechanistic understanding of their activity may support the development of novel targeted and combination anticancer therapies.