Cell Density-Dependent Cytological Stage Profile and Its Application for a Screen of Cytostatic Agents Active Toward Leukemic Stem Cells
PBN-AR
Instytucja
Instytut Immunologii i Terapii Doświadczalnej im. Ludwika Hirszfelda Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
angielski
Czasopismo
STEM CELLS AND DEVELOPMENT (40pkt w roku publikacji)
ISSN
1547-3287
EISSN
1557-8534
Wydawca
MARY ANN LIEBERT INC
DOI
URL
Rok publikacji
2018
Numer zeszytu
7
Strony od-do
488-513
Numer tomu
27
Identyfikator DOI
Liczba arkuszy
Słowa kluczowe
angielski
HL-60
anthrapyridazones
cell culture density-dependent cytological stage profile
drug screening platform
leukemic stem; progenitor and precursor cells
transporter-mediated multidrug resistance
Streszczenia
Język
angielski
Treść
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. In this study, 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. Among the compound tested, C-123 was the most potent against primitive cell stages while generating relatively low amounts of reactive oxygen species (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 allogeneic transplantation and/or ex vivo treatment preceding autologous transplantation.
Cechy publikacji
artykuł oryginalny
Inne
System-identifier
PX-5b28fcc0d5de79ce9d021a76
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