Leukemia Cell Cycle Chemical Profiling Identifies the G2-Phase Leukemia Specific Inhibitor Leusin-1.
Xiaoyu XiaYu-Chen LoAnkur A GholkarSilvia SeneseJoseph Y OngErick F VelasquezRobert DamoiseauxJorge Z TorresPublished in: ACS chemical biology (2019)
Targeting the leukemia proliferation cycle has been a successful approach to developing antileukemic therapies. However, drug screening efforts to identify novel antileukemic agents have been hampered by the lack of a suitable high-throughput screening platform for suspension cells that does not rely on flow-cytometry analyses. We report the development of a novel leukemia cell-based high-throughput chemical screening platform for the discovery of cell cycle phase specific inhibitors that utilizes chemical cell cycle profiling. We have used this approach to analyze the cell cycle response of acute lymphoblastic leukemia CCRF-CEM cells to each of 181420 druglike compounds. This approach yielded cell cycle phase specific inhibitors of leukemia cell proliferation. Further analyses of the top G2-phase and M-phase inhibitors identified the leukemia specific inhibitor 1 (Leusin-1). Leusin-1 arrests cells in G2 phase and triggers an apoptotic cell death. Most importantly, Leusin-1 was more active in acute lymphoblastic leukemia cells than other types of leukemias, non-blood cancers, or normal cells and represents a lead molecule for developing antileukemic drugs.
Keyphrases
- cell cycle
- cell proliferation
- induced apoptosis
- cell cycle arrest
- cell death
- acute lymphoblastic leukemia
- high throughput
- acute myeloid leukemia
- bone marrow
- pi k akt
- single cell
- signaling pathway
- oxidative stress
- emergency department
- stem cells
- small molecule
- allogeneic hematopoietic stem cell transplantation
- drug delivery
- gene expression
- quality improvement
- dna methylation
- genome wide