Triptolide abrogates oncogene FIP1L1-PDGFRalpha addiction and induces apoptosis in hypereosinophilic syndrome.

The pathogenesis of hypereosinophilic syndrome (HES) in some patients is highly dependent on FIP1-Like-1 (FIP1L1)-platelet-derived growth factor receptor alpha (PDGFRalpha), which can generate sustained activation signaling to maintain a cell malignant phenotype. HES usually shows good response to the tyrosine kinase inhibitor imatinib, but mutations in FIP1L1-PDGFRalpha (e.g. T674I) can confer acquired resistance to imatinib. An alternative therapeutic strategy other than with tyrosine kinase inhibitors is needed to overcome acquired drug resistance. We hypothesized that switching off the crucial chimeric oncoprotein FIP1L1-PDGFRalpha on which HES cells depend, should have deleterious effects on the cancer cells. We used low concentrations of triptolide, a transcription inhibitor, to shut down the expression of FIP1L1-PDGFRalpha. EOL-1 cells and BaF3 cells expressing wild-type or T674I FIP1L1-PDGFRalpha were treated with triptolide, and signaling pathways, cell cycling, and apoptosis were analyzed by RT-PCR, immunoblotting, and flow cytometry, respectively. The results revealed that at nanomolar concentrations triptolide decreased the levels of mRNA and protein of FIP1L1-PDGFRalpha and the growth of the neoplastic cells, regardless of the mutational status of PDGFRalpha. Triptolide also downregulated the signaling molecules Stat3, Akt, and Erk1/2, which are downstream from PDGFRalpha, and induced G1 cell-cycle arrest. Triptolide time- and dose-dependently induced apoptosis by decreasing the anti-apoptotic proteins Mcl-1 and Bcl-X(L),triggering the intrinsic apoptotic pathway. In conclusion, triptolide has potent activity against malignant cells in HES bearing FIP1L1-PDGFRalpha, regardless of its mutational status that confer acquired resistance to imatinib. Our results suggest that triptolide may be a promising agent in the treatment of HES.