Flavonoid-Based Combination Therapies and Nano-Formulations: An Emerging Frontier in Breast Cancer Treatment
Abstract
1. Introduction
2. Flavonoids as Natural Therapeutics: Mechanisms and Applications
2.1. Structural Insights into the Chemistry of Flavonoids
2.2. Nature’s Reservoir: Sources of Flavonoids
2.3. Overcoming the Challenges: Bioavailability and Metabolism
3. Epidemiological Studies: Role of Flavonoids in Breast Cancer Prevention
4. Unlocking the Chemotherapeutic Potential of Flavonoids in Breast Cancer Treatment
| Flavonoid | In Vitro/In Vivo | Breast Cancer Cell Lines | Effects | References |
|---|---|---|---|---|
| Hesperidin; Apigenin; Quercetin (Propolis) | In vitro | MCF-7 | Accumulation in G0/G1 phase, cell cycle, proliferation, apoptosis | [115,116] |
| Quercetin | In vitro | MCF-7Ca/TAM-R | Increase in ERα and inhibition of HER2 | [117] |
| Nude/MCF-7 | MCF-7 | Inhibition of von Willebrand Factor (vWF); suppression of calcineurin activity; tumor microvessel density modulation; decrease in VEGF/VEGFR2 signaling and NFAT activation. | [118] | |
| Hesperidin | In vitro | MCF-7 | Increase apoptosis via G0/G1 phase arrest, caspase-3 and caspase-9 upregulation, increase BAX activation, and inhibit BCL-2 expression. | [119] |
| Luteolin | In vitro | MCF-7 | Increase apoptosis via G0/G1 phase arrest, caspase-8 and caspase-9 upregulation and inhibit BCL-2, pAKT, pIGF-1R, Erα expression. | [119] |
| Nude/T47D | T47D | VEGF secretion and mRNA expression, tumor microvessel density, tumor-specific VEGF expression, and BAX levels | [120,121] | |
| Nobiletin | In vitro | MCF-7 | Increase in CYP1 enzyme activity, elevation of CYP1A1 protein expression, upregulation of CYP1B1 mRNA levels, and G1 cell cycle arrest. | [122] |
| Eupatorin | In vitro | MCF-7 | Increased apoptosis in G2/M phase; enhanced activity of BAX, caspase-9, and caspase-8; modulation of RAF-1 and inhibition of VEGFA, BCL2L11, CHK1, CHK2, HIF1A, and AKT | [123] |
| Xanthohumol | In vitro | MCF-7 | Enhance apoptosis during G1 phase arrest while reducing the levels of pAKT (S473); pMAPK (T202/Y204); and phosphorylated ERα at multiple sites (S104/S106, S118, S167, S305, Y537). | [124] |
| Silibinin | In vitro | MCF-7, T47D | Enhanced BAX expression; mitochondrial cytochrome c release; nuclear translocation of AIF; induction of autophagy; activation of caspase-8, and reduced BCL-2 expression; along with modulation of ERα and ERβ activity. | [125,126] |
| Kaempferol | Nude/MCF-7 | MCF-7 | Increase cleaved PARP; BAX and downregulation of BCL-2, pAKT, pMEK1/2, pERK1/2 and pIRS-1. | [127,128] |
| Chalcone; Licochalcone A | In vitro | MCF-7 | Induce plasma membrane damage; BAX upregulation; cleaved PARP, and CIDEA; downregulate G2/M and S cell cycle phases, cyclin-D1, and BCL-2. | [129] |
| LW-214 (flavone) | Nude/MCF-7 | MCF-7 | Enhance BAX expression; cleaved PARP, caspase-9, ROS generation; mitochondrial cytochrome c release; nuclear translocation of AIF, pJNK, and pASK1 levels; reducing BCL-2 and TRX-1 expression. | [130] |
| NSC 686288 (flavone) | In vitro | MCF-7 | Increase cleaved PARP, caspase-9, and ROS levels while decreasing AhR signaling along with the expression of CYP1A1 and CYP1B1. | [131] |
| 2′-Nitroflavone | In vitro | MCF-7 | Cytotoxicity | [132] |
| Pentamethoxylated-flavone | In vitro | MCF-7 | Alters the expression of the BCL-2 protein and promotes cell death. | [133] |
| Puerarin | In vitro | MCF-7, LPS | Decrease NF-κB p65, MMP-9; MMP-2; CCR7; CXCR4; VCAM-1; ICAM-1; TNFα; IL-6; pNF-κB p65; pIκBα; pERK1/2 Downregulate NF-κB MMP-9, p65, CCR7, MMP-2, VCAM-1, TNFα, CXCR4, ICAM-1, pIκBα, p65, IL-6, pNF-κB and pERK1/2. | [134] |
| Calycosin | In vitro | MCF-7, T47D | Decrease FOXP3; MMP-9; VEGF, MMP-9; | [135] |
| Orientin | In vitro | MCF-7, TPA | Reduce IL-8 levels; PKCα membrane translocation; pERK activation, and nuclear translocation of c-JUN, c-FOS, and STAT3. | [136] |
| Corylin | In vitro | MCF-7 | Increase miR-34c and decrease LINC00963 mRNAMMP-9; cytotoxicity | [137] |
| Hinokiflavone | In vitro | MCF-7 | Decrease MMP-9; cytotoxicity | [138] |
| 3,6-Dihydroxy flavone | In vitro | MCF-7 | Upregulation of E-cadherin with downregulation of SNAIL, TWIST, SLUG, N-cadherin, NOTCH1, and NICD. | [139] |
| LFG-500 (Flavone) | MMTV-PyMT transgenic mice | MCF-7 | Upregulation ZO-1; E-cadherin; pYAP; pMST1/2; pLATS1/2 and reduction in N-cadherin; vimentin; SLUG; SNAIL; YAP; ILK | [140] |
| Hispidulin | In vitro | MCF-7 | Upregulation of E-cadherin and downregulation of occludin; pSMAD2/3 | [141] |
| Calycosin | In vitro | Nude/T47D | Upregulation of E-cadherin and downregulation of N-cadherin, vimentin, CD147, MMP-2, MMP-9, and BATF. | [142] |
| 2′-Hydroxy flavanone | Nude/MCF-7 | MCF-7 | Upregulation of E-cadherin and downregulation of vimentin, along with modulation of RLIP76 and ERα expression. | [143,144] |
| Kaempferol | In vitro | MCF-7 | Upregulation of E-cadherin and downregulation of N-cadherin, SNAIL, SLUG, cathepsin D, MMP-9, and MMP-2. | [127,128] |
| Wogonoside | Nude/MCF-7 | MCF-7 | Downregulation of VEGF expression; inhibition of VEGF promoter activity; suppression of endothelial cell (EC) migration; reduction in EC invasion, and impairment of tubulogenesis. | [145] |
| Jaceidin | Swiss albino /Ehrlich Ascites Carcinoma cells | MCF-7 | serum VEGF | [146] |
5. Synergizing Flavonoids with Synthetic Drugs in Combination Therapy
6. Advancement in Flavonoid Nano-Formulations and Codelivery Strategies in Breast Cancer Prevention
7. Safety, Toxicity, and Regulatory Aspects of Flavonoid-Based Nanoformulations
8. Conclusion and Future Perspectives: Advancing Flavonoid Research in Cancer Therapy
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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| Flavonoid | Clinical Trial | Objective of the Study | Clinical Trail Phase | NCT Number | Current Status/Year |
|---|---|---|---|---|---|
| Genistein | Biomarker Assays for a Phase 2 Trial of gemcitabine and genistein in Women with Metastatic Breast Cancer | Explore a target outcome among women with breast cancer at stage IV. The treatment included genistein and gemcitabine hydrochloride. | Phase 2 | NCT00244933 | Completed/2023 |
| The Role of Genistein in Breast Cancer Prevention in Women at elevated risk | Evaluate the role of genistein on the growth of breast epithelial cells isolated from women at elevated risk for breast cancer using a small-needle approach. | Phase 2 | NCT00290758 | Completed/2017 | |
| The Function of Genistein in the Prevention of Breast and Endometrial Cancer in Healthy Postmenopausal Women | Assess the efficacy of genistein in reducing DNA damage and facilitating apoptosis for preventing the development of breast and endometrial cancer in normal postmenopausal women. | Phase 1 | NCT00099008 | Completed/2013 | |
| AFP464, Aminoflavone | Examination of AFP464 and Faslodex in Oestrogen Receptor-Positive Breast Carcinoma | The response to clinical advantage | Phase 2 | NCT01233947 | Terminated/2012 |
| AFP464 in the Management of Patients with Solid tumours That Are Metastatic or Refractory and Unsuitable for Surgical Removal | Examine the disadvantages and ideal dose of AFP464 for patients with solid tumours that are metastatic or resistant to radiation therapy. | Phase 1 | NCT00348699 | Completed/2014 | |
| ME-344 (synthetic molecule having isoflavan ring structure) | ME-344 (57) has anti-angiogenic properties that change mitochondrial metabolism in early HER2-negative breast cancer. | When the mitochondrial phenotype has been produced, determine if adding ME-344 (57) to anti-angiogenic drugs improves anti-tumor action. | Early Phase 1 | NCT02806817 | Completed/2019 |
| Plant extracts | The Function of Plant-Based Dietary Supplements in Intravenous Chemotherapy | Analyze the quantitative effects of dietary supplement consumption on breast cancer patients receiving intravenous infusions of neo-adjuvant and/or adjuvant chemotherapy. | - | NCT03959618 | Completed/2021 |
| Effect of Watercress Consumption on Cancer Patient Results: A Longitudinal Analysis | Examine the possible advantages of therapeutic diets enhanced with watercress-derived nutraceuticals, giving particular attention to how they affect DNA damage and their greater impact on the prognosis of diseases worldwide. | Phase 3 | NCT02468882 | Unknown status/2015 | |
| S-Equol | A Pre-Surgical Clinical Trial Assessing the Efficacy of S-Equol Therapy in Women with Triple-Negative Breast Cancer (TNBC) | To assess the effectiveness of the ERβ agonist S-equol in preventing triple-negative breast cancer (TNBC) cells from proliferating. | Phase 1 | NCT02352025 | Completed/2020 |
| Flavonoids | Effect of Amino Acids and Flavonoids Containing FSMP on Chemotherapy Toxicity, Nutritional Status and Quality of life in Breast Cancer patients | To assess whether an amino acid- and flavonoid-based FSMP with nutritional counseling improves nutritional status, quality of life, and reduces chemotherapy toxicity in breast cancer patients compared to counseling alone. | Not Applicable | NCT05968677 | Recruiting/2025 |
| Hesperidin and Diosmin | The Effect of Oral Administration of Hesperidin and Diosmin in Reducing Paclitaxel-induced Peripheral Neuropathy in Breast Cancer Patients | To evaluate the neuroprotective potential of oral hesperidin and diosmin in reducing paclitaxel-induced peripheral neuropathy in breast cancer patients. | Phase 3 | NCT06811220 | Recruiting/2025 |
| Quercetin | Dasatinib Combined With Quercetin to Reverse Chemo Resistance in Triple-Negative Breast Cancer | To evaluate the efficacy and safety of dasatinib and quercetin in combination with chemotherapy in mTNBC patients who have progressed on prior chemotherapy. | Phase 2 | NCT06355037 | Recruiting/2024 |
| Flavonoids (s) | Synthetic Drug(s)/Combination Agents | Key Patent Claims & Features | Status | Patent Number/Title |
|---|---|---|---|---|
| Isoflavonoids, hydroxyphenyl flavonoids | Kinase inhibitors (nintedanib, dovitinib, regorafenib) | Combination therapies for breast cancer using flavonoids and kinase inhibitors; various dosage forms including oral/IV/topical | Patent granted | ES2877712T3 |
| Luteolin, quercetin, kaempferol | Docetaxel, cisplatin, enzalutamide, radiotherapy | Fixed molar ratio flavonoid blends combined with synthetic chemo/hormonal/radiotherapy; oral and parenteral forms | Patent published | US20170087125A1 |
| Catechins, anthocyanidins, and isoflavones. | Chemotherapeutic agents | Compositions including flavonoids plus chemotherapeutics to enhance anti-cancer effects | Patent granted | US20120213842A1 |
| Flavonoids/antioxidants | Cyclin-dependent kinase (CDK) inhibitors | Therapeutic combinations of flavonoids with CDK inhibitors targeting cancer progression | Patent granted | US10555931B2 |
| Anti-oncogenic flavonoids | Cisplatin, doxorubicin | Novel anti-oncogenic phytochemical combinations with synthetic drugs for cancer treatment | Patent granted | US20240009163A1 |
| Flavonoid mixtures (quercetin, vitamin C, Blueberry Extract) | Methantheline | Flavonoid compositions combined with chemotherapy drugs; methods of use patent | Patent published | WO2017053583A1 |
| Flavonoids/Phenolic Compounds | Anti-Cancer Drug | In Vitro/In Vivo | Cancer Cell Lines/Animal Study | Effect | References |
|---|---|---|---|---|---|
| Luteolin (Flavone) | Tamoxifen | In vitro | MCF-7 | Suppresses Ras expression to cause apoptosis in tamoxifen-resistant ER-positive breast cancer cells. | [187] |
| Doxorubicin | In vitro | MCF-7 | The viability of cells decreased. | [200] | |
| Paclitaxel | In vitro | MDA-MB-231 | Downregulation of BCL-2, mRNA expression | [201] | |
| Quercetin (Flavone) | Docetaxel | In vitro | MDA-MB-231 | Significantly higher BAX levels and upregulated p53 are coupled with decreased expression of the proteins BCL2, pERK1/2, AKT, and STAT3. | [188] |
| 5-fluorouracil | In vitro | MDA-MB-231 | Decreased MMP-2 and MMP-9 gene expression levels and a major decline in migration rate. | [189] | |
| In vitro | MCF-7 | Raising p53, caspase-9 activity, and Bax expression while lowering Bcl2 expression | [90] | ||
| Letrozole | In vitro | MCF-7 | Caused apoptosis produced by the mitochondria and suppressed cellular growth. | [202] | |
| MDA-MB-231 | |||||
| Doxorubicin | In vitro | Doxorubicin MCF-7-resistant | Decreased levels of important genes, such as SNAI2, PLAU, and CSF1, which reverses doxorubicin resistance in breast cancer cells. | [203] | |
| MDA-MB-231 | The MMP-2 and MMP-9 genes showed decreased migration and expression. | [204] | |||
| Genistein (Isoflavone) | Exemestane | In vitro | MCF-7 | Enhanced cytotoxicity | [205] |
| Tamoxifen | In vitro | MCF-7 | Potential to enhance TAM therapy | [190] | |
| Cisplatin | In vitro | Ovariectomized nude mouse breast cancer xenograft model | Enhanced the development of apoptosis and inhibited cell growth. | [191] | |
| ERB-041 | In vitro | CMT-U27; CF41.Mg | Downregulated the expression of ERα, which in turn decreased the regulation of the PI3K/AKT pathway. | [206] | |
| Centchroman | In vitro | MDA-MB-468 MDA-MB-231 MCF-7 | Synergistic anti-cancer potential | [207] | |
| Curcumin (Natural phenol) | Docetaxel | In vitro | MCF-7 | Maximum rates of cytotoxicity, cell apoptosis induction, and cellular uptake | [192] |
| Sorafenib | In vitro | MCF-7 | Apoptotic cell death is induced when vimentin, IL-6, STAT3, and MMP-9 levels are decreased and E-cadherin protein expression is increased. | [193] | |
| Doxorubicin | In vitro | MDA-MB-231 | Indicated that the AKT/mTOR pathway is being suppressed. | [194] | |
| In vitro | MDA-MB-231 MCF-7 | G0/G1 and S-phase cell cycle arrest were associated with enhanced mRNA expressions of the TP53, BRCA1, BRCA2, ATM, and CHEK2 genes (Ct-value). | [195] | ||
| Paclitaxel | In vitro | MCF-7 MDA-MB-231 | Curcumin decreased capacity of M2 TAMs to generate chemoresistance. | [196] | |
| Apatinib | In vitro | MCF-7 | Reduced proliferation and survival | [208] | |
| Celecoxib | In vitro | MDA-MB-231 | Suppressing the COX-2 pathways. | [209] | |
| 5-Fluorouracil | In vitro | MCF-7 | Pro-apoptotic, anti-metastatic, and anti-proliferative. | [210] | |
| Carboplatin | In vitro | CAL-51, CAL-51-R, MDA-MB-231 cells | By enhancing ROS-induced DNA damage, curcumin makes TNBC more susceptible to the anti-cancer effects of carboplatin, offering an efficient combined therapy approach for TNBC. | [197] | |
| Xanthohumol (Prenylflavonoid) | Doxorubicin | In vitro | Doxorubicin-resistant breast cancer cells MCF-7/ADR | Decreased the viability of tumor cells, caused apoptosis, slowed the cell cycle, improved the effects of doxorubicin, decreased stemness, elevated c-H2AX, inhibited STAT3 and EGFR, decreased Bcl-2 and pro-caspase 3, and improved Bax expression. | [211] |
| Doxorubicin-resistant breast cancer cells MCF-7/ADR | Reduced protein expression via inhibiting STAT3 and EGFR, which in turn controlled apoptosis resistance; reduced the expression of MDR1 but not BCRP. | [212] | |||
| Garcinol (Polyphenol) | Paclitaxel | In vivo | 4T1-Luc female Balb/c mice (5–6-weeks-old) | Downregulation of caspase-3, iPLA2, Cyclin A2, Cyclin B1, Cdc25A, Cdc2, Bcl-2, and COX-2, inhibition of paclitaxel-induced NF-κB/Twist1-regulated premetastatic signalling, and lower MMP-2 and MMP-9 activity were observed. | [213] |
| Naringenin | Cyclophosphamide | In vitro | MDA-MB-231 | BAX expression increased whereas Bcl-2 expression decreased. Caspases 3 and 9 were stimulated. | [198] |
| Doxorubicin | In vitro | Breast cancer mouse model | Combination therapy improves anticancer activity in vivo, reducing tumour volume and weight. | [214] | |
| In vitro and In vivo | MDA-MB-231 and 4T1 cells Xenograft mouse model | Increased cytokines (TNF-α and IL-1β) and decreased dose-related body weight loss | [199] | ||
| T47D and MCF-7 cells | In p53-deficient T47D cells, naringenin and hesperidin increased doxorubicin-induced G2/M arrest through a p53-independent pathway. whereas, in p53 wild-type MCF-7 cells, they inhibited G2/M arrest, showing that their anticancer activity is not dependent on cell cycle arrest. | [215] | |||
| Naringin | Capecitabine | In vitro | MCF-7 and SK-BR-3 | Elevation in the Bax/Bcl-2 ratio | [216] |
| Doxorubicin | In vitro | MCF-7 | Significantly raised the level of Bax while inhibiting the expression of STAT3, JAK1, Bcl-2, Survivin, and VEGF. | [217] | |
| 5-Fluorouracil | In vitro | MDA-MB-231 | Reduced cytological toxicity of 5-Fluorouracil | [218] | |
| Mangiferin (Polyphenolic C-glycoside) | Doxorubicin | In vitro | MCF-7 had already received short-term Doxorubicin | Suppressed P-gp expression | [219] |
| Proanthocyanidins (Polyphenols) | Histone deacetylase inhibitor Chidamide | In vitro | T47D and MDA-MB-231 | Suppress the growth and proliferation, while promoting apoptosis | [220] |
| 5-Fluorouracil | MDA-MB-231 | Cell viability and migration declined, apoptosis was induced, cell cycle was arrested in the G2/M phase, generated ROS was increased, mitochondrial membrane potential reduced, the Bax/Bcl-2 ratio was increased, caspase-3 was cleaved, and there was synergistic cytotoxicity with 5-fluorouracil. | [221] | ||
| Apigenin | Doxorubicin | In vitro | DOX resistant MCF-7 cells and MCF-7R | Reduced the phosphorylation and induction of JAK2 and STAT3 proteins. | [105] |
| MCF-7 | Interact with DNA, thus blocking the transcription process | [222] | |||
| Vorinostat | MDA-MB-231 | Increased HAT activity while suppressing DNMT and HDAC enzymatic activity. | [223] | ||
| Kaempferol | Docetaxel | In vitro | MCF-7 | Anti-CSCs agent (decreasing the markers linked to CSCs, such as aldh1a1 and abcb1) | [224] |
| Hesperidin | Doxorubicin | In vitro | Hela Cell Line | Enhanced the expression of Bax and reduced the level of Bcl-2 | [225] |
| MCF-7/HER2 cells | Reduced HER2, Rac1, MMP9 expression, apoptosis, and cell migration after inducing cell cycle arrest | [226] | |||
| MCF-7 resistant doxorubicin cells | Reduced level of Pgp expressions | [227] | |||
| 4T1 | Inhibition of Rac-1 and metalloproteinase-9 expression | [228] | |||
| Tamoxifen | In vivo | xerographic MCF-7 injected rats | Apoptotic genes (Bax, Casp3) are upregulated, while antiapoptotic genes (Bcl-2) and angiogenesis genes VEGF are downregulated. | [229] |
| Nano-Formulation | Flavonoid/Phenolic Compounds | Size (nm) | Effect | References |
|---|---|---|---|---|
| Polymeric nanoformulation | Quercetinhyaluronic acid | 230–480 nm | Prevent tumour development in tumour-developing mice using the passive EPR effect selective targeting mediated by CD44 receptor. | [233] |
| Quercetin–chitosan | <200 | Elevated serum SOD levels | [234] | |
| Quercetin–MPEG-PLA | 155 ± 3 | Induction of cell apoptosis | [235] | |
| Quercetin–Mesoporous silica | <200 | Apoptosis and cell cycle arrest by controlling the AKT and Bax signalling pathways-1. | [236] | |
| EGCG-PEG | 140 ± 7 to 182 ± 13 | Increased expression of p21, PTEN, and Bax, while inhibition of p-AKT, p-PDK1, Bcl-2 and Cyclin D1, reduced cancer cell migration. | [237] | |
| Fisetin–PLA | 225 ± 4 | Enhance the bioavailability and anti-cancer activity of fisetin. | [238] | |
| Lipid –polymer nanoparticles | Quercetin–Mycophenolic acid | 135 ± 10 to 175 ± 30 | Improved pharmacokinetics/pharmacodynamics, reduced first-pass metabolism and displayed additive/synergistic pharmacodynamics. | [239] |
| Solid-lipid nanoparticles | EGCG–Bombesin | 164 ± 2 | Both intrinsic and extrinsic routes can cause apoptosis, which reduces the amount of nutrients that cancer cells receive and prevents migration and angiogenesis. | [240] |
| Gold Nanoparticle | Quercetin–AgFeO2 | 19 | Under UV light, photodynamic therapy reduces cell growth. | [241] |
| Quercetin | 5 | Decreased expression of Vimentin, N-cadherin, Snail, Slug, Twist, MMP-2, MMP-9, p-EGFR, VEGFR-2, p-PI3K, Akt, and p-GSK3β, along with increased expression of E-cadherin protein, substantially decreased epithelial–mesenchymal transition, angiogenesis, and metastasis. | [242] | |
| Hesperidin | 40 | prevent cytokine secretion, including IL-1β, IL-6, IL-8, NO, and TNF-α, causing a rise in ROS. | [243] | |
| Silver Nanoparticles | Apigenin | 94 | Enhance caspase-3 protein, causing apoptosis in tumour cells. | [244] |
| Nano-Formulation | Flavonoid/Phenolic Compounds | Size (nm) | Effect | References |
|---|---|---|---|---|
| Liposomes | Quercetin and vincristine | 130–200 | Co-encapsulated medicines improved quercetin solubility, resulting in synergistic effects and controlled release. | [255] |
| Quercetin and vincristine | 130 | Successful reduction of tumour development in the JIMT-1 patient breast carcinoma xenograft model | [256] | |
| PEGylated Liposomes | Quercetin–Adriamycin (AMD) and doxorubicin | 85 | The combination prevents AMD-induced myelosuppression, elevates white blood cell levels, decreases myocardial cell death due to AMD, and promotes toxicity against resistant tumour cells. | [257] |
| Liposomes | Quercetin and doxorubicin (DOX) | 85 ± 2 | Reduced levels of Nrf2 and its related cytoprotective enzymes, including NQO1 and the drug transporter MRP1, is linked to apoptosis induction. | [258] |
| PLGA-Casein Nanoparticle | EGCG and paclitaxel (PTX) | 190 ± 12 | PTX triggered apoptosis while also suppressing essential genes required for tumour survival. | [259] |
| Lipid Nanoformulation | Silibinin–TPGS | 45 | Reduced levels of MMP-9 and Snails | [260] |
| Albumin based nanoparticles | Epicatechin and morin | 170 ± 6 | Prevent the successful proliferation of cancer cells, leading to cell death. | [261] |
| Nanoparticles based on polyethylene glycol. | Quercetin and Nickel | 50–700 | Reduced mitochondrial membrane potential and increased oxidative stress brought on by an excess of ROS. | [262] |
| Zein-lactoferrin micelles (Lipid nanoparticles) | Rapamycin and wagonin | 277 | Reduced levels of the PI3K-AKT and MAPK pathways, together with anti-angiogenic effects. | [263] |
| AEEAA-PEG-PCL Nanoparticle | Silibinin and IPI-549 | 35–37 | Inhibition of collagen production, angiogenesis, and anti-fibrotic effects in cancerous tissue | [264] |
| pW lipid Nano-particles | Silibinin and cryptotanshinone | 250 | Suppress CD31, TGF-β1, and MMP-9. | [265] |
| Polymeric Nanoparticle | Chyrisin and methotrexate | 198 | Enhanced disruption and cell wall shrinking causes apoptosis. | [266] |
| Chyrisin and curcumin | 400–500 | Upregulation of Cyclin D1, hTERT, Bax/Bcl-2, p53, caspase-3 & 7. | [267] | |
| Zein protein Nanocarrier | EGCG and piperine | 34–80 | The drug is beneficial in NPS because of its higher cellular intake and extended release. | [268] |
| Gold Nanoparticles | EGCG and citrate | 25 | It efficiently controls NF-κB, increasing apoptotic proteins like caspase-3, caspase-7, and Bax and decreasing anti-apoptotic proteins like Bcl2. | [269] |
| Polymeric Nanoparticles | EGCG and curcumin and alpha-tocopheryl succinate | 200–300 | Modified with transferrin and folate, two ligands unique to cancer that support antiproliferative activity. | [270] |
| Nanoemulsion | Baicalein–paclitaxel | 171 ± 6.2 | Decreased glutathione synthesis, and initiated apoptosis | [271] |
| Polymeric Nanoparticles | Quercetin–tamoxifen | >200 | Reduced MMP-2 and MMP-9, enhanced oxidative stress, and decreased GSH caused by lipid peroxidation | [272] |
| Nanoemulsion | Naringenin–tamoxifen | <701 | Reduced P-gp efflux leads to increased anticancer activity. | [273] |
| Nanomicelles | EGCG–Herceptin1 | 100–500 | Extended blood half-life and decreased cancer cell growth. | [274] |
| Polymeric nanoparticles | Quercetin–doxorubicin | 105 | P-glycoprotein expression and function are diminished. | [275] |
| Polymeric Nanoparticles | Quercetin–topotecan | <200 | Cell death occurs when there are significant modifications in the endoplasmic reticulum, mitochondria, and cell wall. | [276] |
| Nanofibers | Quercetin and tamoxifen citrate | Uniform size | The slow process of tumour development | [277] |
| Polymeric Nanoparticles | Genistein–Chitosan–Tamoxifen | 299.8 | The slow process of tumor development | [190] |
| Nanomicelles | Docetaxel and Curcumin | ~64 | The greatest levels of cellular absorption, cytotoxicity, cell apoptosis induction, and reactive oxygen species (ROS) production | [192] |
| Liposomes | Rapamycin–curcumin | Uniform size | Target mTOR to inhibit breast cancer development. | [278] |
| nanocomposites | chitosan/agarose/graphene oxide/montmorillonite–curcumin | Extended release of curcumin to inhibit MCF7 breast cancer cells | [279] | |
| Nanomicelles | Doxorubicin and Curcumin | 187 ± 1.36 | Activated apoptosis and reduced multidrug resistance (MDR) in breast cancer | [280] |
| Nanoparticles | curcumin/Ko143/PLGA | 232.32 ± 10.60 | Promote the intracellular level of the photosensitiser Curcumin (Cur) and improve photodynamic effectiveness by inhibiting the function of efflux pump. | [281] |
| Nanoparticles | Paclitaxel and curcumin | 85.8 ± 0.21 | Showed significant tumour suppression; prevent the formation of P-glycoprotein. | [282] |
| Niosome | Doxorubicin and curcumin | 200 | Regulation of PI3K/Akt/mTOR | [283] |
| Polymeric Micelles | Rutin/Benzoic Acids/Triazolofluoroquinolones | 18 ± 2 | Interaction with the DNA-Topoisomerase I enzyme complex. | [284] |
| Gold nanoparticle | Kaempferol and sorafenib | Uniform size | Enhanced apoptosis rate. | [285] |
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Uniyal, P.; Akhtar, A.; Rawat, R. Flavonoid-Based Combination Therapies and Nano-Formulations: An Emerging Frontier in Breast Cancer Treatment. Pharmaceuticals 2025, 18, 1486. https://doi.org/10.3390/ph18101486
Uniyal P, Akhtar A, Rawat R. Flavonoid-Based Combination Therapies and Nano-Formulations: An Emerging Frontier in Breast Cancer Treatment. Pharmaceuticals. 2025; 18(10):1486. https://doi.org/10.3390/ph18101486
Chicago/Turabian StyleUniyal, Priyanka, Ansab Akhtar, and Ravi Rawat. 2025. "Flavonoid-Based Combination Therapies and Nano-Formulations: An Emerging Frontier in Breast Cancer Treatment" Pharmaceuticals 18, no. 10: 1486. https://doi.org/10.3390/ph18101486
APA StyleUniyal, P., Akhtar, A., & Rawat, R. (2025). Flavonoid-Based Combination Therapies and Nano-Formulations: An Emerging Frontier in Breast Cancer Treatment. Pharmaceuticals, 18(10), 1486. https://doi.org/10.3390/ph18101486

