Evidence of the Beneficial Effects of Ursolic Acid against Lung Cancer
Abstract
:1. Introduction
2. Effects of Ursolic Acid against Lung Cancer
2.1. Effects of Ursolic Acid against Lung Cancer: In Vitro Studies
Cell Type | Dose/Duration | Findings | Mechanism | Reference |
---|---|---|---|---|
A549 | UA 2–40 µM 0–72 h | ↓ Proliferation ↑ Apoptosis G1 phase cell cycle arrest | ↑ p53 protein ↓ Cyclin D1, D2 and E ↑ Fas/APO-1 receptor ↑ FasL ↑ Bax protein ↓ NF-kB/p65 activity ↓ Bcl-2 protein ↓ Bcl-Xl protein | [65] |
H460 | UA 3, 10 and 30 µM 24 h | ↑ Apoptosis ↓ Proliferation ↓ Migration | ↑ Cleaved caspase-3 ↑ MMP 1, 2, 3, 9 and 10 gene expression ↑ Cytosolic glucocorticoid receptor | [66] |
A549 H3255 Calu-6 | UA 2, 4, 8 and 16 µM | ↑ Apoptosis ↓ Cell viability ↓ Cell migration | ↓ NA+-K+-ATPase activity ↓ PKC activity ↓ VEGF protein ↓ ICAM-1 mRNA ↓ Fibronectin mRNA ↓ MMP 2 and 9 mRNA | [67] |
A549 | UA 5–20 µM 24 h | ↓ Proliferation ↓ Cell adhesion ↓ Wound healing ↓ Cell migration | ↑ E-cadherin ↓ N-cadherin ↓ vimentin ↓ AEG-1 ↓ NF-kB | [69] |
A549/H460 | UA 30 µM 12, 24 and 48 h | ↓ Cell viability ↓ Proliferation ↑ Apoptosis ↑ Chromatin condensation | ↑ Cleaved caspase 3/9 ↓ Bcl-2 ↑ Bax ↑ p-AMPK ↓ p-mTOR ↓ ACC activity ↓ FASN l activity | [70] |
A549 | UA 25, 50, 100, 250 and 500 µM | ↓ Cell viability | ↓ VRK1 autophosphorylation ↓ VRK1 activity ↓ p-CREB ↓ p-His-H3 ↓ Cyclin D1 mRNA | [71] |
PC9, H1299, A549, H1650, H358 and H1975 | UA 5, 10, 20, 30, 40, 50 and 80 µM 24, 48 and 72 h | ↓ Cell growth ↑ Apoptosis | ↑ pSAPK/JNK ↓ SP1 protein ↓ DNMT1 protein ↓ EZH2 protein | [72] |
H28, H2452 and MSTO-211H | UA 0–80µM 24–72 h | ↑ Cytotoxicity ↓ Proliferation ↑ Sub-G1 population ↓ EMT | ↑ Cleaved caspase-3 ↑ Cleaved PARP ↑ E-cadherin ↓ N-cadherin ↓ β-catenin ↓ p-GSK2α/β ↓ cyclin D1 ↓ p-AKT ↓ NF-kB | [73] |
A549 | UA 10–100 µM 24 h | ↓ Proliferation ↑ Apoptosis ↑ S-phase cell cycle arrest ↑ Autophagy | ↓ Bcl-2 protein ↑ Cleaved PARP ↑ LC3-II/LC3-I ratio ↑ p62 | [75] |
A549 | UA 11, 22, 44 and 88 µM 24 and 48 h | ↓ Cell viability ↑ Autophagy ↑ Mitophagy | ↑ LC3-II/LC3-I ratio ↑ p62 protein ↑ PINK1 protein ↓ p-AKT ↓ p-mTOR ↑ Nrf2 protein ↑ ROS | [76] |
A549 | UA 5, 10 and 20 µM 24, 48 and 72 h | ↓ Stemness ↓ Chemoresistance | ↓ CD133 ↓ Oct-4 ↓ Notch3 ↓ Nanog ↓ Sox2 | [78] |
H1975 NSCLC with EGFR T790M mutation | UA 1, 5, 25, 50 and 100 µM | ↓ Cell growth ↑ Apoptosis ↓ Cell motility | ↓ CT45A2 mRNA ↓ TCF4 ↓ p-β-catenin @ Ser33/37/Thr41 ↑ p-GSK-3b @ Ser9 | [77] |
H1975 | UA 0.001–0.1 µM | ↓ EMT | ↓ N-cadherin ↑ E-cadherin ↓ MMP-2 and -9 ↓ TGF-β1 | [79] |
NCI-H292 | UA 3, 6, 9, 12 and 15 µM 24 and 48 h | ↓ Cell viability ↑ Apoptosis ↑ Ca2+ production ↓ Mitochondrial membrane potential | ↑ Cleaved caspase-7 ↑ Cleaved PARP ↑ Chromatin condensation ↑ Cytochrome c ↑ endo G ↑ AIF protein ↓ Bcl-2 protein ↓ BID protein | [80] |
A549, H460, H1975, H1299 and H520 H82 and H446 LLC | UA 5–40 µM/ 48 h | ↓ Proliferation ↑ Apoptosis ↑ Autophagy ↓ Cell Viability | ↑ Cleaved PARP ↓ Bcl-2 protein ↑ LC3-II protein ↓ p-S6K @ T389 ↓ p-S6 @ S240-244 ↓ p-4E-BPI @ S65 ↓ p-AKT | [81] |
A549 and H460 | UA 10 and 20 µM | ↓ Proliferation ↑ Apoptosis ↑ G0/G1 cell cycle arrest ↓ Angiogenesis ↓ Migration ↓ Invasion ↓ Tumorsphere formation | ↓ p-EGFR ↓ VEGF ↓ MMP-2 ↓ PD-L1 ↓ CDK4 mRNA and protein ↓ CCND1 mRNA ↓ CCNE1 mRNA ↑ CDKN1A mRNA ↑ CDKN1B mRNA | [82] |
Human bronchial epithelial cells exposed to cigarette smoke extract | UA 3, 6, 12 and 25 µM | ↓ CSE-induced cytotoxicity | ↑ Nrf2 activity | [68] |
H1299 | UA 50 and 80 µM 24 h | ↓ Cell survival ↑ Radiosensitivity | ↓ GSH (intracellular) ↓ HIF-1α protein | [74] |
2.2. Effects of Ursolic Acid against Lung Cancer: In Vivo Studies
2.3. Ursolic Acid Derivatives and Their Effect against Lung Cancer
3. Patent Applications and Clinical Trials Related to Ursolic Acid Use
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
References
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Source | Concentration of UA | Reference | ||
---|---|---|---|---|
Common Name | Botanical Name | |||
Plants | Lavender | Lavandula | 106.7–153.1 mg/g 3.463–6.484 mg/g DW | [36] |
White deadnettle | Lamii albi flos | 39.1–110.4 mg/g DW | [49] | |
Marigold | Calendula officinalis | 20.53 mg/g D.W | [38] | |
Basil | Ocimum tenuiflorum | 20.2 mg/g D.W | [39] | |
Rosinweed, cup plant, compass plant | Silphium sp. flowers | 17.95–22.05 mg/g D.W | [38] | |
Rosemary | Rosmarinus officinalis | 15.8–29.5 mg/g D.W | [40] | |
Daylily | Hemerocallis sp | 0.19 ± 0.05 mg/g DW | [50] | |
Fruits | Black elderberry extract | Sambucus nigra L | 6.62 ± 0.26–0.002 mg/g | [42] |
Olive—adult olive tree leaves | Olea europaea L. | 2.23 ± 0.1 mg/g | [41] | |
Apple—apple peel | Malus | 1.52 mg/g DW | [44] | |
Apple—whole apple | Malus | 0.77 ± 0.1 mg/g to 1.85 ± 0.17 mg/g | [43] | |
Cranberry | Vaccinium macrocarpon | 0.46–1.09 mg/g FW | [45] | |
Pear—mature fruit peel | Pyrus | 0.3481 mg/g | [47] | |
Pear—young fruit | Pyrus | 0.1293 mg/g FW | [46] | |
Olive—virgin olive oil | Olea europaea L. | 0.00138 ± 0.00015 mg/g | [48] |
Xenograft Model | Dose/Duration | Findings | Mechanism | Reference |
---|---|---|---|---|
6–8-week nude mice A549 cells injected subcutaneously | UA—10 mg/kg intragastrical administration/ 1 week | ↓ Tumor volume | Not investigated | [68] |
C57 BL/6 mice injected with LLC-luciferase (1 × 107 cells/mouse) | UA—100 mg/kg intraperitoneally injected | ↓ Tumor volume ↓ Tumor weight | ↓ VRK1 activity | [71] |
Female Balb/c nude mice A549 cells 2 × 106 cells/mouse | UA 50 or 100 mg/kg subcutaneous injection/every other day for 2 weeks | ↓ Tumor growth ↓ Tumor weight | ↓ MMP-2 ↓ Ki-67 ↓ CD34 ↑ Bid | [83] |
Athymic nude mice H1975 cells subcutaneously injected 5 × 106 cells/mouse | UA—25 mg/kg−1 daily for 18 days | ↓ Tumor growth ↓ Tumor weight | Not investigated | [77] |
Athymic Balb/c nude mice A549-PR cells | UA 20 µM 72hr pre-injection co-culture | ↓ Tumorigenesis | Not investigated | [78] |
Cell Line | Derivative Name | Derivative Structure | Findings | Mechanism | Reference |
---|---|---|---|---|---|
A549 SF-295 (CNS) | UA-9 10 nM | ↓ Cell Density | Not investigated | [84] | |
A549 | UA-triazolyl derivative | ↓ Cell Density | Not investigated | [85] | |
A549 | Compound 3B 50 µM, 48h | ↓ Cell Growth | Not investigated | [86] | |
H460 H322 | Compound 17 | ↑ Apoptosis ↑ Autophagy | ↑ Cleaved caspases 8 and 7 ↑ Cleaved PARP ↑ LC3A/B-II ratio ↓ Bcl-2 protein ↓ mTOR protein | [87] | |
A549 H460 | UA232 24, 48 and 72 h | ↑ Cell cycle arrest ↑ Apoptosis ↓ Proliferation | ↓ Cyclin D1 protein ↓ CDK4 protein ↑ CHOP protein ↑ Cleaved PARP | [88] | |
NCI-H460 | 5Y8 5 and 10 µM | ↑ Apoptosis G1 phase cell cycle arrest | ↓ p-NF-kB ↓ p-IKKα/β ↓ TAK1 ↓ TAB1 ↑ ROS | [89] | |
A549 | 8c 5, 10 and 20 µM 24 h | ↑ Apoptosis G1 phase cell cycle arrest ↓ Cell migration | ↑ Caspase-3 cleavage ↓ p-NF-kB ↓ p-IKBα ↓ p-IKKα/β | [90] |
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Kornel, A.; Nadile, M.; Tsiani, E. Evidence of the Beneficial Effects of Ursolic Acid against Lung Cancer. Molecules 2022, 27, 7466. https://doi.org/10.3390/molecules27217466
Kornel A, Nadile M, Tsiani E. Evidence of the Beneficial Effects of Ursolic Acid against Lung Cancer. Molecules. 2022; 27(21):7466. https://doi.org/10.3390/molecules27217466
Chicago/Turabian StyleKornel, Amanda, Matteo Nadile, and Evangelia Tsiani. 2022. "Evidence of the Beneficial Effects of Ursolic Acid against Lung Cancer" Molecules 27, no. 21: 7466. https://doi.org/10.3390/molecules27217466
APA StyleKornel, A., Nadile, M., & Tsiani, E. (2022). Evidence of the Beneficial Effects of Ursolic Acid against Lung Cancer. Molecules, 27(21), 7466. https://doi.org/10.3390/molecules27217466