Phytochemical insights into flavonoids in cancer: Mechanisms, therapeutic potential, and the case of quercetin

Abstract

Quercetin, a flavonoid known for its potent antioxidant and anti-inflammatory properties, has gained attention in cancer therapy due to its ability to modulate key molecular pathways involved in tumor progression and immune evasion. This review provides a comprehensive analysis of quercetin's effects on pathways such as PI3K/Akt/mTOR, MAPK/ERK, NF-κB, and JAK/STAT, which are central to cancer cell survival, proliferation, and apoptosis. Through inhibition of PI3K/Akt/mTOR and MAPK/ERK signaling, quercetin promotes apoptosis and reduces proliferation specifically in cancer cells while sparing healthy cells. Additionally, quercetin downregulates NF-κB activity and modulates JAK/STAT signaling, enhancing immune recognition of cancer cells and decreasing inflammation in the tumor microenvironment. Emerging nanoformulation strategies are also discussed, highlighting how nanotechnology can improve quercetin's bioavailability and targeting capabilities. Unlike other reviews, this work uniquely integrates molecular insights with cutting-edge nanoformulations, showcasing quercetin's dual potential as a therapeutic agent and an immune modulator in the evolving landscape of cancer treatment. This review underscores quercetin's multifaceted role in cancer treatment and suggests future directions to optimize its clinical efficacy, particularly in combination with conventional therapies.

Keywords: Antioxidants; Flavonoids; JAK/STAT; NF-κB; Nanoformulations; PI3K/Akt/mTOR; Quercetin; Signaling pathways; Tumor microenvironment.

Fig. 1

Phenolic rings of the basic structure of flavonoids. Image designed and adapted from Kopustinskiene et al. [34].

Fig. 2

Key signaling pathways modulated by QRT during cancer prevention and its regulation of miRNAs across various cancer types. (A) Wnt/β-catenin pathway: QRT inhibits β-catenin nuclear translocation. (B) PI3K/Akt pathway: QRT blocks phosphorylation of PI3K, Akt, and S6K. (C) JAK/STAT pathway: QRT suppresses phosphorylation of STAT proteins. (D) MAPK pathway: QRT induces phosphorylation of p38, JNK, and ERK. (E) p53 pathway: QRT promotes phosphorylation of p53, activating apoptosis. (F) QRT's regulation of miRNAs (↑ increased, ↓ decreased) and its therapeutic effects on various cancer types, including osteosarcoma, ovarian, colon, oral, pancreatic, lung, breast cancer, and leukemia. Effects include reduced differentiation, proliferation, metastasis, angiogenesis, and drug resistance, while promoting apoptosis and cell cycle arrest. Reprinted/adapted with permission from Asgharian et al. [142]. Copyright 2022, Cancer Cell International from BMC - part of Springer Nature (Open Access).

Fig. 3

(Left) Effect of green tea (GT), QRT (Q), and arctigenin (Arc) on prostate tumorigenesis: (A) Study design. (B) In vivo imaging shows tumor inhibition, most notable in the GT + Q + Arc group. (C) Quantification of tumor signal intensity. (D–F) No differences in food, water intake, or body weight were observed. (Right) Pathological analysis: (A) Representative prostate images show reduced tumor size in GT + Q + Arc. (B) Prostate weight normalized to body weight. (C) H&E staining reveals reduced tumor grade in treatment groups, especially GT + Q + Arc. No metastasis was detected. Reprinted/adapted with permission from Hao et al. [143]. Copyright 2024, Biomolecules from MDPI (Open Access).

Fig. 4

Schematic representation of niosome encapsulation and preparation process. (Top) Structural diagram of a niosome showing the arrangement of hydrophilic and hydrophobic compounds within the bilayer membrane composed of non-ionic surfactants and cholesterol. Hydrophilic compounds are encapsulated in the aqueous core, while hydrophobic compounds are integrated within the lipid bilayer. (Bottom) Process flow for niosome preparation using tangential flow and high-pressure homogenization. The aqueous phase and lipid dispersed phase are combined under controlled conditions using nitrogen pressure, followed by tangential flow filtration through a pressurized vessel to form niosomes. Reprinted/adapted with permission from Liga et al. [196]. Copyright 2024, Pharmaceutics from MDPI.

Fig. 5

(Left) (A) Preparation process of PAQNPs. (B) Mechanism of PAQNPs in regulating energy metabolism to reverse multidrug resistance in ovarian cancer. (Right) (A) Treatment protocol for the A2780/Taxol tumor-bearing NCG mice model. (B) Tumor volume progression under different treatments. (C) Tumor images post-dissection. (D) Final tumor weights. (E) TUNEL and H&E staining of tumor tissues. (F) IHC analysis of P-gp expression in tumors. Scale bars: 50 μm. Reprinted/adapted with permission from Lu et al. [202]. Copyright 2024, International Journal of Pharmaceutics from ElSevier.