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2015 ; 5
(ä): 14391
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Longitudinal tracking of single live cancer cells to understand cell cycle
effects of the nuclear export inhibitor, selinexor
#MMPMID26399741
Marcus JM
; Burke RT
; DeSisto JA
; Landesman Y
; Orth JD
Sci Rep
2015[Sep]; 5
(ä): 14391
PMID26399741
show ga
Longitudinal tracking is a powerful approach to understand the biology of single
cells. In cancer therapy, outcome is determined at the molecular and cellular
scale, yet relationships between cellular response and cell fate are often
unknown. The selective inhibitor of nuclear export, selinexor, is in development
for the treatment of various cancers. Selinexor covalently binds exportin-1,
causing nuclear sequestration of cargo proteins, including key regulators of the
cell cycle and apoptosis. The cell cycle effects of selinexor and the
relationships between cell cycle effects and cell fates, has not been described
for individual cells. Using fluorescent cell cycle indicators we report the
majority of cell death after selinexor treatment occurs from a protracted
G1-phase and early S-phase. G1- or early S-phase treated cells show the strongest
response and either die or arrest, while those treated in late S- or G2-phase
progress to mitosis and divide. Importantly, the progeny of cell divisions also
die or arrest, mostly in the next G1-phase. Cells that survive selinexor are
negative for multiple proliferation biomarkers, indicating a penetrant, arrested
state. Selinexor acts quickly, shows strong cell cycle selectivity, and is highly
effective at arresting cell growth and inducing death in cancer-derived cells.