Chalcone Derivatives: Role in Anticancer Therapy
Abstract
:1. Introduction
2. Strategies Employed to Produce Anticancer Chalcones
2.1. Naturally Occurring Chalcones
2.2. Synthetic Chalcone Derivatives
2.3. Chalcone Hybrids
2.3.1. Artemisinin–Chalcone Hybrids
2.3.2. Chalcone–Azole Hybrids
2.3.3. Chalcone–Coumarin Hybrids
2.3.4. Chalcone–Indole Hybrids
3. Representative Mechanisms of Anticancer Action of Chalcones
3.1. Chalcones Target the p53 Pathway
Lead Compounds | Mechanisms of Action | Reference |
---|---|---|
Trans-chalcone (1) | Enhances the expression of HSP40 and inhibits CRM1, thereby blocking MDM2-mediated ubiquitination of p53 and enhancing p53 accumulation in the nucleus. | Silva et al. [128,130] |
2-fluoro-4’-aminochalcone (47a) and 3-pyridyl-4’-aminochalcone (47b) | Induces apoptosis by up-regulating p53 expression and without Sp1 expression alteration in MCF-7 cells | Dos Santos et al. [129] |
Trans-chalcone (1) | Induces death by autophagy mediated by p53 up-regulation and Wnt/β-catenin down-regulation on human hepatocellular carcinoma HuH7.5 cell line | Siqueira et al. [131] |
Chalcone derivative 4′-aminochalcone (48) | Suppresses migration and invasion of osteosarcoma cells mediated by p53 regulating EMT-related genes | Seba et al. [132] |
Coumarlcone hybrid (39, S009-131) | Instigates DNA damage, disrupts p53-MDM2 interaction and stabilizes p53 through post-translational modifications in both vitro and vivo of HeLa cells | Sashidhara et al. [81,82] |
(E)-3-(3, 5-di-ter-butyl-4-hydroxyphenyl)-1-(4-hydroxy-3-methoxyphenyl) prop-2-en-1-one (49, LQFM064) | Induces cell cycle arrest at the G0/G1 phase with up-regulation of p53 and p21 | Cabral et al. [133] |
3.2. Chalcones Target Tubulin Polymerization
3.3. Chalcones and the NF-κB Pathway
3.4. Chalcones as Inhibitors of Angiogenesis
3.5. Chalcones as Inhibitors of MDR Channels
Lead Compounds | Mechanisms of Action | Reference |
---|---|---|
2-[3-(4-Dimethylaminophenyl)-prop-2-en-yliden]-5,6- dimethoxyindan-1-one (69) | Inhibitors of human P-glycoprotein | Parveen et al. [176] and Ngo et al. [177] |
Bifendate chalcone hybrids (70) | P-gp inhibitors in K562/A02 cells whichoverexpress P-gp (induced by adriamycin) | Gu et al. [178] |
MY3 (71) | Inhibits expression of P-gp and enhances the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells | Yin et al. [179] |
Flavokawain A (FKA) (72) | Inhibits P-gp protein expression by blocking the PI3K/Akt pathway in PTX-resistant lung cancer A549 cells | Li et al. [180,181] |
Licochalcone A (LCA) (73) | Binds ABCG2 in the transmembrane substrate-binding pocket and reverses ABCG2-mediated multidrug resistance in human multidrug-resistant cancer cell lines | Wu et al. [182] |
Quinazoline chalcones (74) | Modulators of breast cancer resistance protein (BCRP/ABCG2) in P-gp overexpressing MDCK II cells | Kraege et al. [114] |
Symmetric bis-chalcones (75) | Inhibits mitoxantrone efflux from ABCG2-transfected HEK293 cells by stimulating ABCG2 basal ATPase activity | Winter et al. [183] |
Tariquidar-related chalcones (76) | ABCG2 Modulators in ABCG2-overexpressing MCF-7/Topo cells | Peña-Solórzano et al. [109] |
Quinolone chalcones (77) | Targets colchicine-binding pocket and kills multidrug-resistant cancer cells by inhibiting tubulin activity and MRP1 function | Lindamulage et al. [111] |
A novel chalcone derivative, JAI-51 (78) | A microtubule-depolymerizing agent and an inhibitor of P-gp and BCRP in vitro and in vivo of glioblastoma models | Boumendjel et al. [184] |
Nonbasic chalcone (79) | A dual ABCG2/ABCB1 inhibitor in S1-M1-80 (mitoxantrone (MX)-selected ABCG2-overexpressing of human colorectal cancer cell line S1), NCI-H460/MX20 (MX-selected ABCG2-overexpressing of human lung cancer cell line NCI-H460) | Han et al. [185] and Cai et al. [186] |
Novel chalcone and flavone derivatives (80) | Selective and dual inhibitors of the transport proteins ABCB1 and ABCG2 in ABCG2-overexpressing MDCK II BCRP cells | Silbermann et al. [99] |
3.6. Other Molecular Cancer Targets Modulated by Chalcones and Target Identification
4. Summary and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Lead Compounds | Mechanisms of Action | Reference |
---|---|---|
CA-4 type chalcones SD400 (50) and α-phenyl chalcone (51) | Populate the colchicine-binding site of beta-tubulin and inhibit tubulin assembly in the K562 human chronic myelogenous leukemia cell line | Ducki et al. [135,136] |
A series of phenstatin/isocombretastatin–chalcones (52) | Inhibit tubulin assembly, arrest in the G2/M phase and induce apoptosis in a panel of sixty human cancer cell lines | Kamal et al. [137] |
Phenstatin based indole linked chalcone compounds (53) | Destabilizes tubulin, leading to loss of cell integrity and affecting glucose metabolism in SCC-29B human oral cancer cells, spheroids and AW13516 oral cancer xenograft model mice | Kode et al. [138] |
Chalcone-1,2,3-triazole derivative (54) | Inhibits tubulin polymerization in liver cancer HepG2 cells | Yan et al. [139] |
(E)-3-(3-amino-4-methoxyphenyl)-1-(5’-methoxy-3’,4’-methylendioxyphenyl)- 2-methylprop-2-en-1-one (55, TUB091) | Destabilizes microtubule, targets vascular and shows antitumor and antimetastatic activities in melanoma and breast cancer xenograft models | Canela et al. [140] |
Triazoloquinoxaline-chalcone derivatives (56) | Displays significant antiproliferative effects against MCF-7, HCT-116 and HEPG-2 cells | Alswah et al. [141] |
2-arylbenzo[c]furan-chalcone hybrids (57) | Inhibits tubulin polymerization and EGFR-TK phosphorylation in the human breast cancer (MCF-7) cell line | Mphahlele et al. [98] |
Lead Compounds | Mechanisms of Action | Reference |
---|---|---|
Butein (7) | Blocks the phosphorylation and degradation of IκBα and suppresses NF-κB activity in KBM-5 (human myeloid) cells | Pandey et al. [147] |
2-hydroxy-3’,5,5’-trimethoxychalcone (58, DK-139) | Inhibits the Akt//IKK/NF-κB signaling pathway in BV2 microglial cells | Lee et al. [148] |
(E)-1-(2-hydroxy-6- (isopentyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (59) | Inhibits NF-κB activity in vitro and shows antiproliferative activity against various human cancer cell lines, namely ACHN (renal), NCI-H23(lung), MDA-MB-231 (breast), HCT-15 (colon), NUGC-3 (stomach) and PC-3 (prostate). | Venkateswararao et al. [158] |
Dihydrotriazine-chalcone compounds (60) | Inhibits IKKα/β phosphorylation, leading to a reduction in phosphorylation of the p65 subunit and eventually suppression of NF-κB-dependent transcriptional activation of MMP-9 expression. in MDA-MB-231 breast carcinoma cells | Gan et al. [159] |
Lead Compounds | Mechanisms of Action | Reference |
---|---|---|
3′,5′-diprenylated chalcone (61) | An Fli-1 agonist for regulating the expression of Fli-1 target genes including VEGF-1, TGF-β2 and MMP-1 genes of prostate cancer cells | Ma et al. [163] |
Flavonoids (62) isolated from young Caesalpinia bonduc twigs and leaves | A molecular docking analysis shows the interaction between them and cancer target proteins (TK, VEGF, and MMP) | Iheagwam et al. [164] |
Isoliquiritigenin (6, ISL) | Inhibits the angiogenic Akt- FGF-2/TGF-β/VEGF signaling in C6 glioma cell line and the rat C6 glioma model. | Wang et al. [28] |
Isoliquiritigenin (6, ISL) | Inhibits VEGF expression via promoting HIF-1α proteasome degradation pathway and blocks VEGFR-2 activation and the transduction of its downstream signaling in human umbilical vein endothelial cells (HUVECs), MCF-7 cells and MDA-MB-231 cells and in vivo tumor xenograft of MDA-MB-231 cells | Wang et al. [165] |
Licochalcone E (63, LicE) | Decreases expression of VEGF-A and C, VEGF receptor 2, and HIF-1α in the mouse model of breast cancer | Kwon et al. [166] |
Xanthohumol (64) | Inhibits angiogenesis by suppressing NF-κB activation and the subsequent production of angiogenic factors VEGF and IL-8 in vitro and in vivo of pancreatic cancer (BxPC-3) | Saito et al. [167] |
Chalcone-based compounds with 2,2-dimethylbenzopyran (65) | Inhibits HIF-1 by downregulating the expression of HIF-1α in Hep3B and HUVEC cells and Hep3B xenograft models | Wang et al. [168] |
2, 3’, 4, 4’-tetrahydroxy-3, 5’-diprenylchalcone (66, FLA-16) | Inhibits CYP4A and prolongs survival and normalizes vasculature in C6 and U87 gliomas tumor models through decreasing production of TAMs and EPCs-derived VEGF and TGF-b. | Wang et al. [169] |
Analog of chalcone (67) | Suppresses TGF β1, induces EMT markers, MMP 2 and MMP 9, and inhibits migration and invasion of A549 cells | Jeong et al. [170] |
Anthraquinone-chalcone hybrids (68) | Decreases in the expression levels of MMP2, MMP9, and VEGF in K562 cells | Stanojkovic et al. [171] |
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Ouyang, Y.; Li, J.; Chen, X.; Fu, X.; Sun, S.; Wu, Q. Chalcone Derivatives: Role in Anticancer Therapy. Biomolecules 2021, 11, 894. https://doi.org/10.3390/biom11060894
Ouyang Y, Li J, Chen X, Fu X, Sun S, Wu Q. Chalcone Derivatives: Role in Anticancer Therapy. Biomolecules. 2021; 11(6):894. https://doi.org/10.3390/biom11060894
Chicago/Turabian StyleOuyang, Yang, Juanjuan Li, Xinyue Chen, Xiaoyu Fu, Si Sun, and Qi Wu. 2021. "Chalcone Derivatives: Role in Anticancer Therapy" Biomolecules 11, no. 6: 894. https://doi.org/10.3390/biom11060894
APA StyleOuyang, Y., Li, J., Chen, X., Fu, X., Sun, S., & Wu, Q. (2021). Chalcone Derivatives: Role in Anticancer Therapy. Biomolecules, 11(6), 894. https://doi.org/10.3390/biom11060894