| Properties | Information | |
|---|---|---|
| PhytoCAT-ID | PhytoCAT-376 | |
| Phytochemical name or plant extracts | Ursolic acid | |
| PMID | 23479388 | |
| Literature evidence | Most of these compounds showed significant cytotoxic activities against four human cancer cell lines (A549, HCT116, MDA-MB-231, and CCRF-CEM), and the structure-activity relationships are also discussed. | |
| IUPAC name | (1S,2R,4aS,6aR,6aS,6bR,8aR,10S,12aR,14bS)-10-hydroxy-1,2,6a,6b,9,9,12a-heptamethyl-2,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydro-1H-picene-4a-carboxylic acid | |
| Phytochemicals’ class or type of plant extracts | Triterpenoid | |
| Source of phytochemicals or plant Extracts | Prinsepia utilis | |
| Geographical availability | Assam, China South-Central, East Himalaya, India, Myanmar, Nepal, Pakistan, Tibet, West Himalaya | |
| Plant parts | Aerial parts | |
| Other cancers | Breast cancer, Lung cancer, Colon cancer, Leukemia, Liver cancer , Stomach cancer, Cervical cancer, Liver cancer | |
| Target gene or protein | Fas receptor, Caspase 8, Caspase 3, Caspase 9, PARP, Bax, Bcl-2, cyt-c, Nrf2, NQO1, Keap1, miR-499a-5p, mTOR, AKT, MMP2, u-PA, NF-κB, Cyclin D, Cyclin E, CDK4, CDK2, PI3K, AKT, ERK, FoxO1/FoxO3a, DR4, DR5, Cyclin D1, PCNA, p21Waf1/Cip1, PLK1, CCNB1, ABCC1, MiR-186-5p, MAPK1/3, ABCG2 | |
| Gene or Protein evidence | In our study, we found that ursolic acid induced the appearance of Fas receptor and cleavage of caspase-8, -3 and PARP. We also found that ursolic acid induced Bax up-regulation and Bcl-2 down-regulation and release of cytochrome C to the cytosol from mitochondria. Moreover, ursolic acid cleaved caspase-9 and decreased mitochondrial membrane potential (ΔΨm) as shown with JC-1 staining. The expressions of Nrf2 and p-Nrf2, in whole cell and nucleus, and NQO1 were inhibited by UA treatment, whereas the Keap1 expression was upregulated. Furthermore, expression of the oncogenic miR-499a-5p was substantially diminished in CSCs after UA treatment. In conclusion, we demonstrated that the anti-invasive effects of ursolic acid on MDAMB231 cells might be through the inhibition of Jun N-terminal kinase, Akt and mammalian target of rapamycin phosphorylation and a reduction of the level of NFkappaB protein in the nucleus, ultimately leading to downregulation of MMP-2 and u-PA expression. In MCF-7 cells, UA increased p53 and p21 expression but decreased cyclin D, cyclin E, CDK4, and CDK2 expression to induce cell cycle arrest in the G0/G1 phase. Moreover, UA significantly suppressed migration, invasion, and colony formation in MCF-7 cells, and suppressed mammosphere formation in a concentration- dependent manner. In MCF-7 cell-derived BCS-like cells, UA significantly decreased migration, suppressed p-PI3K, p-AKT, and p-ERK expression, and enhanced p-FoxO1/FoxO3a expression. Tumor cell selective apoptotic action of UA was mainly attributed due to the activation of extrinsic apoptosis pathway via up regulation of DR4, DR5 and PARP cleavage in MCF-7 cells over non-tumorigenic MCF-10A cells. Western blotting analysis revealed that S9 fraction and UA significantly induced PCNA, CDK4, and Cyclin D1 downregulation in MDA-MB-231 cells, followed by p21Waf1/Cip1 up-regulation. In vivo and in vitro experiments showed that UA could inhibit the growth of TNBC cells, and down-regulate the protein expression levels of PLK1 and CCNB1 by mediating p53 signaling pathway. Mechanistically, multidrug resistance-associated protein 1 (ABCC1) expression was downregulated by UA treatment. MiR-186-5p was verified to target ABCC1. Further, UA-inhibited ZEB1-AS1 (zinc finger E-box binding homeobox 1 antisense RNA 1) was verified as a competitive endogenous RNA (ceRNA) to upregulate ABCC1 through sponging miR-186-5p. Activation of MAPK1/3 but not inhibition of MTOR pathway contributed to UA-induced cytoprotective autophagy in MCF-7 cells. Of the non-flavonoid phytochemicals tested, berberine, celastrol, ellagic acid, limonin, oleanolic acid, propyl gallate, sinapic acid and ursolic acid demonstrated significant inhibition of ABCG2-mediated transport. | |
| Target pathways | PI3K/AKT and NF-κB signaling pathway Nrf2 Pathway Keap1/Nrf2 pathway EGFR/Nrf2 pathway Wnt/β-catenin pathway c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling ERK and PI3K/AKT Signaling Pathway p53 signaling pathway ZEB1-AS1/miR-186-5p/ABCC1 signaling | |
| IC50 | 10.7 µg/mL against MCF-7 1.49 µg/mL against MDA-MB-231 4.1 μM aginst SKBR-3 | |
| Potency | These results suggest that ursolic acid has potential as a chemopreventive agent for metastatic breast cancer. UA promotes TNBC cell sensitivity to DOX through inactivating ZEB1-AS1/miR-186-5p/ABCC1 signaling. | |
| Cell line/ mice model | A549, HCT116, MDA-MB-231, and CCRF-CEM, 4T1, ,MCF-7, BEL-7402, SPC-A-1, SGC-7901, HeLa, HT-29 , Caco-2, HepG2, HT-29, HDFn, SKBR-3, HeLa S3, KB, HL60, MDA-MB-468, Hep3B | |
| Additional information | Shows significant cytotoxic activities against four human cancer cell lines (A549, HCT116, MDA-MB-231, and CCRF-CEM) Causes upregulation of glycogen synthase kinase activity (P<0.05) and downregulation of B-cell lymphoma 2 (P<0.05), subsequently causing autophagy and apoptosis via cyclin-D1 inhibition and caspase-3 stimulation (P<0.05), downregulates NF-κB in breast cancer cells Inhibits expressions of Nrf2 and p-Nrf2, NQO1 and upregultes expression of Keap1, abolishes EGF-induced p-Nrf2 and its downstream NQO1 and SOD1 enzymes (MDA-MB-231) Suppresses miR-499a-5p and upregulates the Wnt antagonist, sFRP4 (in CSCs) Induces cell G1/G2 arrest UA-liposomesinhibit STAT5 phosphorylation and IL-10 secretion (IN VIVO - 4T1 TUMOR BEARING MOUSE), reduce numbers of myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) Shows great binding affinity towards P38Map Kinase with binding energy = -9.97 kJ/mol Reduces the levels of NFkappaB p65, c-Jun and c-Fos proteins, causes inhibition of Rho-like GTPases, growth factor receptor-bound protein 2, Ras and vascular endothelial growth factor in cytosol, causes downregulation of MMP-2 and u-PA expression and supresses the phosphorylation of Jun N-terminal kinase, Akt and mammalian target of rapamycin (MDAMB231 cells) Induces apoptosis bysuppressing the expression of FoxM1 and inactivation of CyclinD1/CDK4(MCF-7 cells) Increases p53 and p21 expression but decreasedscyclin D, cyclin E, CDK4, and CDK2 expression to induce cell cycle arrest in the G0/G1 phase, causes reduced phosphorylation of PLK1 (MCF-7 cells) Suppresses p-PI3K, p-AKT, and p-ERK expression, and enhanced p-FoxO1/FoxO3a expression (MCF-7 cell-derived BCS-like cells) Mediates intracellular ROS generation and mitochondrial membrane potential disruption Decreases the levels of NOP2, proliferation-associated nucleolar protein p120, and WDR12, causes nucleoplasmic translocation of RNA polymerase I-specific transcription initiation factor RRN3/TIF-IA, inhibition of new rRNA synthesis, elevation of p21 levels Causes inhiibiton of TNF-α, IL-1β, IL-6, and IFN-γ production Induces PCNA, CDK4, and Cyclin D1 downregulation in MDA-MB-231 cells, followed by p21 Waf1/Cip1 up-regulation Induces cytoprotective autophagy via activation of MAPK1/3 (MCF-7) Causes ATM activation and AMPK activation-mediated cytotoxic response, decreases pERK1/2 signals Causes down-regulation of CXCR4, uPA, vimentin, E-cadherin, N-cadherin, and MMP-2/9 proteins expression (in combination with Met) (MDA-MB-231, MCF-7 cells) Decreases the levels of NOP2, proliferation-associated nucleolar protein p120, and WDR12 | |
| PubChem ID | 64945 | |
| Additional PMIDs | 32523377 21910059 29042957 32551573 33278391 27469428 31926193 34336607 24374448 16450302 24658565 17488026 20352621 21191671 35047440 16968064 29568181 27453990 28334682 28839362 30676770 27492128 28025124 28025124 32523377 34858165 23497885 33493421 23182854 28213701 29227654 27708244 34371592 28334682 32674610 22855944 25046839 21058195 | |
| Additional sources of information | https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:437543-1 | |
| Safety | NA |