Abstract
Background FF-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 −resistant acute myelogenous leukemia (AML) cell lines. Methods We 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. Results FF-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. Conclusions FF-10501-01 effectively induces AML cell death and reduces AML peripheral blood cell proliferation by targeting guanine nucleotide biosynthesis regardless of HMA resistance status.
Original language | English (US) |
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Pages (from-to) | 85-92 |
Number of pages | 8 |
Journal | Leukemia Research |
Volume | 59 |
DOIs | |
State | Published - Aug 2017 |
Keywords
- Acute myeloid leukemia
- Guanosine
- HMA resistance
- IMPDH
- Metabolic inhibitor
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research