Abstract
BackgroundRelapsed leukemia following initial therapeutic response andremission is difficult to treat and causes high patient mortality. Leukemiarelapse is due to residual quiescent leukemia cells that escape conventionaltherapies and later reemerge. Eliminating not only growing but quiescentleukemia cells is critical to effectively treating leukemia and preventing itsrecurrence. Such dual targeting therapeutic agents, however, are lacking in theclinic. To start tackling this problem, encouraged by the promising anticancereffects of a set of curcumin derivatives in our earlier studies, we examined inthis work the effects of a 4-arylmethyl curcumin derivative (C212) ineliminating both growing and quiescent leukemia cells.MethodsWe analyzed the effects of C212 on the growth and viability ofgrowing and quiescent leukemia cells using MTS, apoptosis, cell cycle and celltracking assays. The effects of C212 on the quiescence depth of leukemia cellswere measured using EdU incorporation assay upon growth stimulation. Themechanisms of C212-induced apoptosis and deep dormancy, particularly associatedwith its inhibition of Hsp90 activity, were studied using molecular docking,protein aggregation assay, and Western blot of client proteins.ResultsC212, on the one hand, inhibits growing leukemia cells at a higherefficacy than curcumin by inducing apoptosis and G2/M accumulation; it, on theother hand, eliminates quiescent leukemia cells that are resistant toconventional treatments. Furthermore, C212 drives leukemia cells into and killsthem at deep quiescence. Lastly, we show that C212 induces apoptosis and drivescells into deep dormancy at least partially by binding to and inhibiting Hsp90,leading to client protein degradation and protein aggregation.ConclusionC212 effectively eliminates both growing and quiescent leukemiacells by inhibiting Hsp90. The property of C212 to kill quiescent leukemia cellsin deep dormancy avoids the risk associated with awaking therapy-resistantsubpopulation of quiescent leukemia cells during treatments, which may lead tothe development of novel therapies against leukemia relapse.FU_qv23TkQH-xJX8jq2RAYVideo abstract
Highlights
Relapsed leukemia following initial therapeutic response and remission is difficult to treat and causes high patient mortality
In leukemia cells (HL60 and K562), the mean IC50 ratio (C212 vs. curcumin) was 0.16 as compared to 0.27–0.50 in other cancer cell types (Table 1), and the mean AUC ratio (C212 vs. curcumin) was 0.75 as compared to 0.80–0.95 in other cancer cell types (Table 1). These results indicated that leukemia cells underwent stronger growth-inhibition effects than other cancer cells did under C212
In this study, we found that C212, a 4-arylmethyl curcumin derivative demonstrates a dual anticancer effect against leukemia cells: it inhibits cell growth by inducing apoptosis and G2/M accumulation, but eliminates quiescent cells that are resistant to conventional chemotherapy drugs such as paclitaxel, doxorubicin, and topotecan, as well as the targeted therapy Midostaurin
Summary
Relapsed leukemia following initial therapeutic response and remission is difficult to treat and causes high patient mortality. Eliminating growing but quiescent leukemia cells is critical to effectively treating leukemia and preventing its recurrence. Such dual targeting therapeutic agents, are lacking in the clinic. Quiescent cancer cells, including but not limited to cancer stem cells, escape conventional chemotherapies; they often reemerge after a period of dormancy, causing cancer relapse and metastasis that are exceedingly difficult to treat and lead to high patient mortality [6,7,8]. We identified two natural compounds, ergosterol peroxide and ganodermanondiol, from the medical mushroom Ganoderma lucidum [15] We showed that these two compounds eliminated quiescent slow-cycling cells by pushing cells to shallow quiescence and exposing them to cytotoxic effects [15]. If some of these quiescent cancer cells develop and acquire therapy resistance during dormancy [4, 10], waking them can be risky
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