Lica 2018 Stem Cells Dev
|Lica JJ, Grabe GJ, Heldt M, Misiak M, Bloch P, Serocki M, Switalska M, Wietrzyk J, Baginski M, Hellmann A, Borowski E, Skladanowski A (2018) Cell density-dependent cytological stage profile and its application for a screen of cytostatic agents active towards Leukemic Stem Cells. Stem Cells Dev 27:488-513.|
Abstract: Proliferation and expansion of leukemia is driven by Leukemic Stem Cells (LSCs). Multidrug resistance (MDR) of LSCs is one of the main reasons of failure and relapses in Acute Myeloid Leukemia (AML) treatment. Here we show that maintaining HL-60 at low cell culture density or applying a 240-day treatment with anthrapyridazone (BS-121) increased the percentage of primitive cells which include LSCs determining the overall stage profile. This change manifested in: morphology, expression of both cell surface markers and redox-state proteins as well as mitochondrial potential. Moreover, four sublines were generated, each with unique and characteristic stage profile and cytostatic sensitivity. Cell density-induced culture alterations (affecting stage profiles) were exploited in a screen of anthrapyridazones. Amongst the compound tested, C-123 was the most potent against primitive cell stages while generating relatively low amounts of ROS. Furthermore, it had low toxicity in vivo and weakly affected blood morphology of healthy mice. The cell density-dependent stage profiles could be utilized in preliminary drug screens for activity against LSCs or in construction of patient-specific platforms to find drugs effective in case of AML relapse (drug extrapolation). The correlation between ROS generation in differentiated cells and toxic effect observed in HL-60 has a potential application in myelotoxicity predictions. The discovered properties of C 123 indicate its potential application in AML treatment, specifically in conditioned myeloablation preceding allogenic transplantation and/or ex vivo treatment preceding autologous transplantation.
• Keywords: Drug screening platform, Cell culture density-dependent cytological stage profile, Anthrapyridazones, C-123, Reactive oxygen species (ROS), ATP-binding cassette transporter-mediated multidrug resistance, Leukemic stem, Progenitor and precursor cells, Human acute myeloid leukemia cell line, HL-60 • Bioblast editor: Kandolf G
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Cancer
Organism: Human, Mouse Tissue;cell: Heart, Blood cells, Other cell lines
Coupling state: LEAK, ROUTINE, ET Pathway: N HRR: Oxygraph-2k