Abstract
Background
Relapsed leukemia following initial therapeutic response and
remission is difficult to treat and causes high patient mortality. Leukemia
relapse is due to residual quiescent leukemia cells that escape conventional
therapies and later reemerge. Eliminating not only growing but quiescent
leukemia cells is critical to effectively treating leukemia and preventing its
recurrence. Such dual targeting therapeutic agents, however, are lacking in the
clinic. To start tackling this problem, encouraged by the promising anticancer
effects of a set of curcumin derivatives in our earlier studies, we examined in
this work the effects of a 4-arylmethyl curcumin derivative (C212) in
eliminating both growing and quiescent leukemia cells.
Methods
We analyzed the effects of C212 on the growth and viability of
growing and quiescent leukemia cells using MTS, apoptosis, cell cycle and cell
tracking assays. The effects of C212 on the quiescence depth of leukemia cells
were measured using EdU incorporation assay upon growth stimulation. The
mechanisms of C212-induced apoptosis and deep dormancy, particularly associated
with its inhibition of Hsp90 activity, were studied using molecular docking,
protein aggregation assay, and Western blot of client proteins.
Results
C212, on the one hand, inhibits growing leukemia cells at a higher
efficacy than curcumin by inducing apoptosis and G2/M accumulation; it, on the
other hand, eliminates quiescent leukemia cells that are resistant to
conventional treatments. Furthermore, C212 drives leukemia cells into and kills
them at deep quiescence. Lastly, we show that C212 induces apoptosis and drives
cells into deep dormancy at least partially by binding to and inhibiting Hsp90,
leading to client protein degradation and protein aggregation.
Conclusion
C212 effectively eliminates both growing and quiescent leukemia
cells by inhibiting Hsp90. The property of C212 to kill quiescent leukemia cells
in deep dormancy avoids the risk associated with awaking therapy-resistant
subpopulation of quiescent leukemia cells during treatments, which may lead to
the development of novel therapies against leukemia relapse.