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.