ptc-209 and Leukemia--T-Cell

B cell-specific Moloney murine leukemia virus integration site 1 (BMI1) is up-regulated in several cancers; therefore, we investigated the effects of BMI1 inhibitors on leukemia cells.. Four acute myeloid leukemia and two T-lymphoblastic leukemia cell lines were treated with BMI1 inhibitors artemisinin, PRT4165, and PTC-209 and analyzed for cell proliferation and gene expression by microarray and immunoblotting.. PTC-209 and PRT4165 suppressed the growth of all cell lines through apoptosis.Artemisinin acted only on Jurkat cells. BMI1 inhibitors and BMI1-specific siRNA down-regulated the expression of NOTCH signaling proteins NOTCH1, HES1, and MYC. All but one cell lines did not have the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene targeted by BMI1, thus the inhibitors acted through CDKN2A-independent pathways.. BMI1 inhibition suppressed proliferation of leukemia cells through NOTCH signaling which functions downstream of BMI1, suggesting that BMI1 inhibitors can be candidate targeted drugs against leukemia.

Topics: Apoptosis; Cell Proliferation; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 2-Ring; Humans; Leukemia, Myeloid, Acute; Leukemia, T-Cell; Polycomb Repressive Complex 1; Receptors, Notch; RNA, Small Interfering; Signal Transduction; Thiazoles; Tumor Cells, Cultured