| RRC ID |
86045
|
| Author |
Liu W, Jiang Z, Wang R, Zhang X, Jiang X, Chen C, Guo P, Yi M, Li W.
|
| Title |
Targeting EGFR-Mcl-1 Axis by Piperlongumine as a Novel Strategy for Non-Small Cell Lung Cancer Therapy.
|
| Journal |
Am J Chin Med
|
| Abstract |
Non-small cell lung cancer (NSCLC) is a malignancy that faces serious resistance challenges in treatment. In this study, we identified Piperlongumine as a promising therapeutic candidate to overcome Osimertinib resistance in NSCLC. We systematically investigated the inhibitory effect of Piperlongumine on NSCLC cells and confirmed that it could effectively inhibit the in vitro kinase activity of wild-type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. We also found that Piperlongumine-induced intrinsic apoptosis by interfering with the EGFR signaling pathway, which was characterized by the down-regulation of the anti-apoptotic protein Mcl-1. Further mechanistic studies revealed that Piperlongumine-induced degradation of Mcl-1 was dependent on the Akt-GSK3β signaling pathway. Additionally, Piperlongumine-promoted interaction between Mcl-1 and β-TRCP, thereby enhancing β-TRCP-mediated ubiquitination and the degradation of Mcl-1. Furthermore, Piperlongumine significantly inhibited tumor growth in both Osimertinib-sensitive and resistant NSCLC xenograft models. These findings highlight the potential of Piperlongumine as an effective agent in overcoming EGFR-targeted therapy resistance and suggest new avenues for its clinical application in NSCLC treatment.
|
| Volume |
53(2)
|
| Pages |
597-619
|
| Published |
2025-1-1
|
| DOI |
10.1142/S0192415X25500235
|
| PMID |
40145280
|
| MeSH |
Acrylamides / pharmacology
Aniline Compounds / pharmacology
Animals
Apoptosis / drug effects
Apoptosis / genetics
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / metabolism
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Line, Tumor
Dioxolanes* / pharmacology
Dioxolanes* / therapeutic use
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
ErbB Receptors* / genetics
ErbB Receptors* / metabolism
Humans
Indoles
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Lung Neoplasms* / pathology
Mice
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein* / genetics
Myeloid Cell Leukemia Sequence 1 Protein* / metabolism
Phytotherapy*
Piperidones
Pyrimidines
Signal Transduction* / drug effects
Signal Transduction* / genetics
Xenograft Model Antitumor Assays
|
| IF |
3.682
|
| Resource |
| Human and Animal Cells |
Ba/F3 |
