Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms
Abstract
:1. Introduction
2. Quercetin and Breast Cancer (BC)
2.1. Quercetin Free Form in BC Experimental Models
2.2. Effects of Combination of First-Line Treatments with Quercetin in BC Experimental Models
2.3. Delivery Systems for Quercetin in BC Experimental Models
3. Quercetin and Colorectal Cancer (CRC)
3.1. Quercetin Free Form in CRC Experimental Models
3.2. Effects of Combination of First-Line Treatments with Quercetin in CRC Experimental Models
3.3. Delivery Systems for Quercetin in CRC Experimental Models
4. Quercetin and Hepatocellular Cancer (HCC)
4.1. Quercetin Free Form in HCC Experimental Models
4.2. Effects of Combination of First-Line Treatments with Quercetin in HCC Experimental Models
4.3. Delivery Systems for Quercetin in HCC Experimental Models
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cell [or Animal] Model | Concentration | Effect | Reference |
---|---|---|---|
MDA-MB-468 | 23–55 µM | Arrest of cells in G2/M phase and growth inhibition | [36] |
MCF-7 | 17.2 µM | Reduction in cell growth | [37] |
MCF-7 | 4.9 µM | Counteractive effects on pro-proliferative effects of E2 and TNF- α | [38] |
MCF-7 | 1–20 µM | Induction of apoptosis and arrest of cells in G2/M phase (p21 dependent) | [39] |
MCF-7 | 48 µM | Increased ROS production | [40] |
MCF-7 | 100 µM | Increased ROS production; induction of apoptosis; AMPK activation and decrease of COX-2 protein levels | [41] |
MCF-7 | 100 µM | Reduction in proliferation | [42] |
MCF7, T47D (ER+) MDA-MB-231, HCC-38 (ER−) | 0.1–60 µM | (ER+): pro-proliferative effects at lower concentrations; anti-proliferative effects at higher concentrations (ER−): anti-proliferative effects | [43] |
MCF-7, MDA-MB-231 | 5–20-100 µM | Lower concentrations: pro-proliferative effects Higher concentrations: anti-proliferative effects | [44] |
MCF-7, SK-Br-3 | 100 µM | Induction of c-fos; activation of MEKs and ERK1/2; EGFR and MAPK activation | [45] |
MCF-7 | 0.1–1000 nM | Increase in PTEN protein level; decrease in phosphorylated AKT; increase in p27; arrest of cell cycle | [46] |
HCC1937 (PTEN−/−), T47D (PTEN+/+) | 25 µM | Reduction in phosphorylated AKT level | [47] |
MCF-7, MDA-MB-231 | 30 µM [50 mg/kg] | Decrease in cellular invasion and migration capacities; decrease in AKT/mTOR activity; autophagy induction; decrease in GLUT1, PKM2, LDHA; reduction in tumor volume | [48] |
BCSC (CD44+ from MCF-7) [xenograft] | 50 µM | Reduction in cell viability and metastatic properties; reduction in tumor volume | [50] |
HCC1806, HCC70, HCC1937, BT-549, BT-20, Hs578T, MDA-MB231, MDA-MB 157 and MDA-MB-468 BT-549 | 200 µM | Migration inhibition and decreased invasion abilities; decreased AKT phosphorylation; decrease in GSK3α/β and WNK-1; reduced phosphorylation of β-catenin, ERK1/2, JNK1/2/3, p38α; increase in CHK2 phosphorylation | [51] |
MDA-MB-231, MDA-MB-435 | 15 µM | Increase in AMPK phosphorylation; decrease in AKT activity; growth inhibition and arrest of cell cycle in G2/M phase | [52] |
MDAMB-231, MDA-MB-157 | 230, 415 µM | Reduced lipid synthesis; inhibition of FAS; reduction of cell viability and induction of apoptosis; decrease in FASN, β-catenin, Bcl-2 | [55] |
MCF-7 | Increased level of phosphorylated AMPK; decreased level of phosphorylated AKT | [57] | |
MDA-MB-231 | 20 µM | Decreased cell viability; increased apoptosis; cell cycle arrest; JNK and FOXO3a increase | [58] |
MCF-7, MDA-MB-231 [xenograft] | Induction of apoptosis; negative regulation of EGFR; increase in miR-146a expression; reduction in tumor volume | [59] | |
MCF-7, MDA-MB-231 | 100 µM | Reduction in HSP70 and HSP27, HSP90 protein levels | [60,61] |
BCSC ALDH+, AS-B145, AS-B244 | 0–200 µM | Reduction in HSP27; decrease in mammosphere dimension, cell migration and EMT; decrease in nuclear translocation of NF-κB and proteasomal degradation of IκBα HSP27-mediated | [63] |
MDA-MB-231 | 150 µM | Growth inhibition; decrease in intracellular calcium concentration; decrease in urokinase activity | [64] |
TNBC MDA-MB-231 | 25 µM | Reduction in PFKP and LDHA protein levels; decrease in cellular invasiveness and migration | [65] |
Cell [or Animal] Model | First-Line Agent | Effect of Combination | Reference |
---|---|---|---|
MCF7-DR | Docetaxel | Synergistic increase in cytotoxicity; decrease in Lef1 | [67] |
MDA-MB-231 | Docetaxel | Synergistic induction of apoptosis; increase in p53 and BAX; decrease in pAKT, pERK1/2, pSTAT3 | [68] |
EMT6 [xenograft] | Cisplatin | Greater cytotoxic effects; reduction in tumor volume | [69] |
MDA-MB-231 | 5-fluorouracil | Greater decrease in cell viability and migration; decrease in MMP-2 and -9 expression | [70] |
MCF-7 | 5-fluorouracil | Synergistic increase in apoptosis | [71] |
MCF-7, BT-20 | rhTRAIL | Enhancement of apoptosis; induction of proteasomal degradation; reduction in c-FLIP and increase in DR5 | [72] |
MCF-7/ADR | Paclitaxel | Downregulation of P-glycoprotein | [73] |
MCF-7/ADR | Doxorubicin, paclitaxel, vincristine | Enhancement of cytotoxic effects; decrease in P-glycoprotein protein level and YB-1 nuclear translocation | [74] |
Cell [or Animal] Model | Delivery System | Effect | Reference |
---|---|---|---|
MCF-7/ADR | Encapsulated quercetin and paclitaxel in MSNs-ChS@PQ | Augmented cytotoxicity and apoptosis | [75] |
MDA-MB-231/MDR1 | Encapsulated quercetin and doxorubicin in mixed micelles of HA-based conjugate and d-α-tocopheryl poly-(ethylene glycol) 1000 succinate | More efficient induction of apoptosis | [76] |
4T1 [xenograft] | Encapsulated quercetin in nanoparticles of RSF coated with LyP-1-QU-NPs | Greater inhibition of cell viability; stronger apoptosis induction; reduced tumor volume | [77] |
MCF-7 | Nanoparticles of apoferritin loaded with quercetin and curcumin | Increase in ROS production and apoptosis induction | [79] |
MCF-7 | Solid lipid nanoparticles loaded with quercetin and curcumin | Increase in ROS production and apoptosis induction | [80] |
4T1 | Nanoparticles formed by PLGA, linked to PEI, and bound to HA of quercetin and docetaxel | Decrease in phosphorylated AKT and MMP-9 protein level; decrease in NF-κB activity | [81] |
MCF-7, MDA-MB-231 | Quercetin-conjugated gold nanoparticles | Decreased EMT, migration and invasion abilities; strong inhibition of PI3K/AKT pathway; reduction in EGFR activity | [85] |
Cell (or Animal) Model | Concentration | Effect | Reference |
---|---|---|---|
SW480/ mouse CRC clone 26 | 60/160 µM | Reduction in cell growth; cell cycle blockage | [87] |
Caco-2 | 5–50 µM | Reduction in cell growth; downregulation of cell cycle-related factor mRNAs | [88] |
HT-29 | 15 µM | Cell growth inhibition | [86] |
HT-29, HCT-116 | 0–70 µM | Pro-proliferative effects | [42] |
HT-29, COLO205, COLO205-X | 200 µM | Reduction in cell viability | [89] |
HT-29 [xenograft] | 100 µM [50–100 mg/kg] | Growth inhibition; chromatin condensation; cell cycle arrest in G1 phase; AMPK activation; induction of apoptosis | [91] |
HT-29 | 1–100 µM | COX-2 protein level decrease; induction of apoptosis; increase in IκBα expression | [41,92] |
Caco-2, SW620 | 35–20 µM | Growth inhibition; induction of caspase-dependent apoptosis; reduction in p65 and IκBα phosphorylated protein levels; increase in IκBα expression | [93] |
HCT116, HT-29 | 25–50 µM | ROS production; apoptosis induction; increase in sestrin2 | [96,98] |
DLD-1 | 1 µM | Induction of apoptosis by activation of ERβ1; increased p38MAPK phosphorylated and PTEN expression; PI3K/AKT/mTOR pathway activation | [101] |
HCT116 [xenograft] | 100 µM [50 mg/kg] | Apoptosis induction; inhibition of AMPK activity; reduction in tumor volume and AMPK phosphorylation | [102] |
HT-29 | 81.65 µM | Induced strong cellular morphological changes and apoptosis; modulation of CSN6 activity | [103] |
HT-29, SW480 | 100 µM | Induction of apoptosis; decrease in ErbB2 (HER2) and 3 (HER3); decrease in PI3K activation | [104] |
Caco-2, DLD-1 | 50 µM | Up-regulation of CB1-R; inhibition of growth; inhibition of PI3K/AKT activity; JNK and c-Jun activation | [105,106] |
[AOM/DSS-induced CRC] | [30 mg/kg] | Decrease in tumor size and volume | [107,108] |
HCT-116 | 40 µM | Increase in NAG-1 expression; increase in SP1 and EGR-1 transcription factors | [109] |
DLD-1 | 20 µM | TNF-alpha-stimulated COX-2 expression | [110] |
Caco-2 | 5 µM | Inhibition of TLR-4 and NF-κB activity | [111] |
SW480 | 100 µM | Inhibition of TGF-β1-induced EMT; increase in E-cadherin; decrease in vimentin and Twist1 | [112] |
HCT-15, CO-115 | 20 µM | Apoptosis induction; inhibition of RAS and PI3K activity | [114] |
SW480, HCT116, DLD-1KRASG13D | 100 µM | Induction of extrinsic and intrinsic apoptosis; inhibition of AKT and activation of JNK | [115] |
Cell [or Animal] Model | First-Line Agent | Effect of Combination | Reference |
---|---|---|---|
HCT-15 | 5-fluorouracil | Enhancement of caspase-independent apoptosis | [120] |
HT-29 | 5-fluorouracil | Increase in apoptosis induction | [121,126] |
HT-29 | 5-fluorouracil | Increase in p53 expression; decrease in AKT and mTOR pathways | [122] |
DLD-1 [Xenograft] | Ionizing radiation | Reduction in tumor volume | [123] |
HT-29 | Cisplatin | Reduction in cell viability; induction of apoptosis and cell cycle blockage | [124] |
CSC | Doxorubicin | Enhancement of cytotoxic activity and cell arrest in G2/M phase | [124,125] |
Cell [or Animal] Model | Delivery System | Effect | Reference |
---|---|---|---|
CT26-FL3 [xenograft] | Encapsulation of quercetin and alantolactone in micelles of DSPEPEG2000 and TPGS | Greater cytotoxicity (IC50 drop from 148 to 8 µM); reduction in tumor volume; decrease in mTOR phosphorylation | [127] |
[CRC rats] | Nanoparticles of quercetin cross-linked to chitosan | Reduction in tumor angiogenesis and mitosis rate; increase in apoptosis | [128] |
HCT-8/TAX | Encapsulated doxorubicin and quercetin in hollow mesoporous silica nanoparticles, coated with polydopamine bound to mPEG-NH2 | Better uptake; decrease in P-glycoprotein protein level | [129] |
Caco-2 | Encapsulated quercetin in chitosan nanoparticles coated with sodium alginate by coaxial electrospinning | Increase in growth inhibition; induction of apoptosis; arrest in G0/G1 phase | [130] |
Cell (or Animal) Model | Concentration | Effect | Reference |
---|---|---|---|
KIM-1, KYN-1, -2, -3, HAK-1A, -1B, -2, -3, -4, -5, and -6 | 50–100 µM | Growth inhibition; apoptosis induction; cell cycle blockage | [131] |
HepG2 | 40 µM | Apoptosis induction; increase in intracellular ROS dependent on upregulation of PIG3 expression | [132] |
Huh-7, HepG2 | 80 µM | Decrease in ROS; decrease in PI3K p85α subunit phosphorylation, total PKC activity, PKCα and COX-2 protein level; increase in p53 | [133,134] |
HepG2 | 50 µM | JNK activation; decreased ERK and AKT phosphorylation level; decreased nuclear translocation of NF-κB; increased nuclear translocation of AP-1 | [139] |
LM3 (Xenograft) | 90 µM (100 mg/kg) | Growth inhibition; autophagy and apoptosis induction; decrease in invasiveness, EMT and migration; reduced JAK2 and STAT3 phosphorylation levels | [140] |
SMMC-7721, HepG2 (Xenograft) | 40 µM (100 mg/kg) | Autophagy induction by inhibition of AKT/mTOR pathway and increase in MAPKs activities | [141] |
Huh-7 | 7–30 µM (+HGF or +TNF-α) | Reduced cell migration, PI3K/AKT pathway; E-cadherin increase | [142] |
Bel-7402, SMMC-7721 (Xenograft) | <50 µM (50 mg/kg) | Inhibition of cell viability, downregulation of HK2 | [143] |
Huh-7 | 82.7 µM | Increased expression of miR-1275; degradation of IGF2BPs mRNA | [146] |
HepG2 | 12.9 µM | Downregulation of Sp1 | [147] |
HepG2 | 50 µM | Induction of apoptosis; influence of chymotrypsin-like proteasomal activity; ERK1/ERK2 decreased activity; decrease in proteasome β expression | [148] |
HepG2 | 40 µM | Increase in aggregation of F-actin, cytoskeleton disruption and membrane perturbation | [149] |
(HCC-induced mice) | (100 or 25 mg/mL, before or after HCC induction, respectively) | Normalization of hepatic enzymes; reduction in liver oxidative stress; decrease in CK2-α and Notch and Hedgehog pathways | [150] |
Cell [or Animal] Model | First-Line Agent | Effect of Combination | Reference |
---|---|---|---|
HepG2, Hep3B | Sorafenib | Combination or pre-treatment with quercetin lowered sorafenib IC50 | [151] |
HepG2, MDBK, Huh-7 | Celecoxib | Growth inhibition and apoptosis induction | [152] |
SMCC-7721, HepG2 (Xenograft) | 5-fluorouracil | Decrease in cell growth by apoptosis induction; reduction in tumor volume | [153] |
HepG2 | Cisplatin | Induction of growth inhibition and apoptosis | [154] |
HepG2, Hep3B | Roscovitine | Induction of growth inhibition; decrease in AKT phosphorylation; pro-apoptotic protein levels increase | [155] |
HepG2/GEM | Gemcitabine | Decrease in cell viability and higher apoptosis rate | [156] |
HepG2 (3D) | Doxorubicin | Induction of apoptosis | [158] |
SMMC-7721, HepG2, Huh-7 (Xenograft) | ZD55 adenovirus | Reduction in cell growth and tumor volume | [159] |
HepG2, Huh-7 | Interferon-α | Increase in anti-proliferative effects; inhibition of SHP2 | [160] |
Cell (or Animal) Model | Delivery System | Effect | Reference |
---|---|---|---|
HepG2.2.15 | Encapsulated quercetin and superparamagnetic iron oxide nanoparticles into micelles | Decrease in the concentration needed to arrest cell cycle | [161] |
HepG2 | Encapsulated quercetin in nanoparticles formed by PLGA decorated with chitosan and PEG | Stronger reduction in cell viability compared to quercetin free form; induction of apoptosis | [162] |
HepG2 | Encapsulated quercetin in solid-lipid nanoparticles of cholesterol | More efficient reduction in cell growth compared to free-form quercetin | [163] |
HepG2 (Xenograft) | Encapsulated quercetin and sorafenib in modified lipid nanoparticles coated with RGD | Inhibition of cell growth; reduction in tumor volume | [164] |
MHCC97H, Hep3B, HCCLM3 and Bel7402 | PLGA encapsulated gold quercetin nanoparticles | Increase in growth inhibition; reduction in both PI3K/AKT and MEK/ERK pathway activities; hTERT reduced level; inhibition of COX-2 expression; reduction in NF-κB nuclear translocation; downregulation of AP-2β signaling; reduced tumor volume | [165] |
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Maugeri, A.; Calderaro, A.; Patanè, G.T.; Navarra, M.; Barreca, D.; Cirmi, S.; Felice, M.R. Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms. Int. J. Mol. Sci. 2023, 24, 2952. https://doi.org/10.3390/ijms24032952
Maugeri A, Calderaro A, Patanè GT, Navarra M, Barreca D, Cirmi S, Felice MR. Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms. International Journal of Molecular Sciences. 2023; 24(3):2952. https://doi.org/10.3390/ijms24032952
Chicago/Turabian StyleMaugeri, Alessandro, Antonella Calderaro, Giuseppe Tancredi Patanè, Michele Navarra, Davide Barreca, Santa Cirmi, and Maria Rosa Felice. 2023. "Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms" International Journal of Molecular Sciences 24, no. 3: 2952. https://doi.org/10.3390/ijms24032952