| Properties | Information | |
|---|---|---|
| PhytoCAT-ID | PhytoCAT-60 | |
| Phytochemical name or plant extracts | Nimbolide | |
| PMID | 31209351 | |
| Literature evidence | Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. | |
| IUPAC name | methyl 2-[(1R,2S,4R,6R,9R,10S,11R,15R,18R)-6-(furan-3-yl)-7,9,11,15-tetramethyl-12,16-dioxo-3,17-dioxapentacyclo[9.6.1.02,9.04,8.015,18]octadeca-7,13-dien-10-yl]acetate | |
| Phytochemicals’ class or type of plant extracts | Terpenoid | |
| Source of phytochemicals or plant Extracts | Azadirachta indica | |
| Geographical availability | Assam, Bangladesh, Cambodia, Laos, Myanmar, Thailand, Vietnam | |
| Plant parts | Leaves | |
| Other cancers | Breast cancer, Leukemia, Lung cancer, Colorectal cancer | |
| Target gene or protein | p21, Bax, Bad, Fas-L, TRAIL, FADDR, cyt-c, Bcl-2, Bcl-xL, Mcl-1, XIAP-1, pro-caspase 8, pro-caspase 3, integrin αV, integrin β3, ILK, FAK, PAK, DNMT-1, HDAC-6, miR-21, HOTAIR, H19, miR-148a/miR-152, PTEN, ABCB1/MDR1 mRNA, P-gp, HIF1α, FoxO1, MYC | |
| Gene or Protein evidence | Nimbolide impairs breast cancer cell proliferation in-part by disrupting RNF114-substrate recognition, leading to inhibition of ubiquitination and degradation of tumor suppressors such as p21, resulting in their rapid stabilization. These events were associated with: increased levels of proapoptotic proteins Bax, Bad, Fas-L, TRAIL, FADDR, cytochrome c and reduced levels of the anti-apoptotic proteins Bcl-2, Bcl-xL, Mcl-1 and XIAP-1. Nimbolide induces the cleavage of pro-caspase-8, pro-caspase-3 and PARP. The above data suggest that nimbolide induces apoptosis by both the intrinsic and extrinsic pathways. Furthermore, analysis revealed that integrins αV and β3, ILK, FAK, and PAK levels were downregulated by nimbolide. Downregulation of DNMT-1, HDAC-6, miR-21, HOTAIR, and H19 with upregulation of miR-148a/miR-152 indicated that nimbolide regulates AR and IGF-1/PI3K/Akt signaling via epigenetic modifications. The P-glycoprotein (ABCB1/MDR1)-overexpressing CEM/ADR5000 cell line displayed remarkable hypersensitivity to nimbolide, which was mediated through upregulation of the tumor suppressor, PTEN, and its downstream components resulted in significant downregulation in ABCB1/MDR1 mRNA and P-glycoprotein. In addition, nimbolide targeted essential cellular metabolic-regulating elements including HIF1α, FoxO1, MYC and reactive oxygen species. | |
| Target pathways | Extrinsic and intrinsic pathway Integrin and FAK signaling pathway AR and IGF-1/PI3K/Akt signaling | |
| IC50 | NA | |
| Potency | With evidence of above data it is suggested that nimbolide exhibit anticancer effect through its apoptosis-inducing property. Thus, nimbolide raises new hope for its use in anticancer therapy. In conclusion, our data demonstrate that nimbolide inhibits TNBC by altering the integrin and FAK signaling pathway. | |
| Cell line/ mice model | MDA-MB-231, HCC38, HEK293T, MCF-7, HL-60, SMMC7721, A549, SW-480 | |
| Additional information | We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Nimbolide inhibited cell proliferation, migratory, and invasive abilities of TNBC cells and also changed the shape of MDA-MB-231 cells, which is correlated with cytoskeletal changes including actin depolymerization. | |
| PubChem ID | 12313376 | |
| Additional PMIDs | 23089555 25377085 24888707 29778718 30515268 31632020 31209351 33768141 35125086 21674442 | |
| Additional sources of information | https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:1213180-2 | |
| Safety | NA |