Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5527751 | Leukemia Research | 2017 | 8 Pages |
â¢FF-10501-01 induces AML leukemic cell death and reduces cell proliferation.â¢FF-10501-01 shows strong anti-leukemia effect regardless of HMA resistance status.â¢FF-10501-01 functions through targeting guanine nucleotide biosynthesis.
BackgroundFF-10501-01 is a selective inosine monophosphate dehydrogenase (IMPDH) inhibitor that has shown activity in cancer cell lines. We studied whether FF-10501-01 is effective in targeting a variety of hypomethylating agent (HMA)-sensitive and âresistant acute myelogenous leukemia (AML) cell lines.MethodsWe treated multiple cell lines (including HMA-resistant cells) with FF-10501-01 and analyzed proliferation, apoptosis, and cell cycle status. We also assessed HMA-FF-10501-01 combinations and the ability of extracellular guanosine to rescue cell proliferation in FF-10501-01-treated cells. We performed high-performance liquid chromatography (HPLC) to study guanine nucleotide levels in treated and untreated cells. Finally, we studied the effects of FF-10501-01 in fresh peripheral blood cells taken from AML patients.ResultsFF-10501-01 showed a strong dose-dependent effect on proliferation and induced apoptosis at approximately 30 μM. The effects of FF-10501-01 treatment on cell cycle status were variable, with no statistically significant trends. Guanosine rescued proliferation in FF-10501-01-treated cells, and HPLC results showed significant decreases in phosphorylated guanosine levels in MOLM13 cells. FF-10501-01 effectively reduced proliferation at concentrations of 300 μM and above in 3 primary AML samples.ConclusionsFF-10501-01 effectively induces AML cell death and reduces AML peripheral blood cell proliferation by targeting guanine nucleotide biosynthesis regardless of HMA resistance status.