Inhibitory effect of the anthelmintic drug pyrvinium pamoate on T315I BCR-ABL-positive CML cells

Abstract

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by a chromosome translocation that generates the BCR‑ABL oncogene, which encodes a constitutively activated tyrosine kinase. Despite progress in controlling CML at the chronic phase by first and second generations of BCR‑ABL tyrosine kinase inhibitors (TKIs), effective drugs with good safety are not available for CML patients harboring T315I BCR‑ABL and those in advanced stages of CML. Therefore, there is an urgent requirement for the development of effective therapies against T315I BCR‑ABL. In the present study, it was demonstrated that pyrvinium pamoate, an anthelmintic drug approved by the Food and Drug Administration had potent inhibitory effects on growth and survival in CML cells with T315I BCR‑ABL. In addition, this agent was equally effective in inhibiting the Wnt/β‑catenin signaling in wild‑type and T315I BCR‑ABL CML cells. Thus, the clinical efficacy of pyrvinium pamoate in treating patients with CML bearing T315I BCR‑ABL should be further investigated.

Overexpression of miR-4433 by suberoylanilide hydroxamic acid suppresses growth of CML cells and induces apoptosis through targeting Bcr-Abl

“…Imatinib-sensitive CML cells KBM5 expressing wild-type Bcr-Abl were cultured in Iscove's modified Dulbecco's medium (Invitrogen, Shanghai, China) supplemented with 10% fetal bovine serum. Imatinib-resistant CML cells KBM5-T315I bearing a substitution of threonine-to-isoleucine at 315 codon were maintained in the same medium as KBM5 but with 1.0 μM imatinib, which was removed before experiments with a wash-out periods of 2-3 days 18. Cells in logarithmic phase were used in all experiments starting with 2 × 10 5 cells/ml.…”

“…Cell viability was evaluated by MTS assay (CellTiter 96 Aqueous One Solution Cell Proliferation assay; Promega, Madison, WI) as previous described 18. 100 μl cells (2× 10 5 cells/ml) were seeded in 96-well plates and incubated with various concentrations of SAHA for 72 hours.…”

“…Western blotting was performed using standard methods as previously described 18. Whole cell lysates were prepared in radio-immunoprecipitation assay buffer (1× PBS, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS) supplemented with freshly added 10 mM β-glycerophosphate, 1 mM orthovanadate, 10 mM NaF, 1 mM phenylmethylsulfonyl fluoride, and 1 × Roche Complete Mini Protease Inhibitor Cocktail.…”