Curcumin derivative C212 inhibits Hsp90 and eliminates both growing and quiescent leukemia cells in deep dormancy

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.

Analysis of Dormancy-Associated Transcriptional Networks Reveals a Shared Quiescence Signature in Lung and Colorectal Cancer

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Curcumin in treatment of hematological cancers: Promises and challenges

“…Besides, curcumin is able to reduce levels of HSP90 in mediating protein degradation and aggregation, and suppressing progression rate of leukemia cells. 43 BCAT1 and mTOR are related to apoptosis in leukemia. Curcumin-mediated inhibition of BCAT1 and mTOR triggers apoptosis in leukemia cells.…”

Role of natural products in tumor therapy from basic research and clinical perspectives

“…Similarly, curcumin and its analogs also exhibit chemopotentiating properties in other leukemia subtypes, such as CLL and CML [242,243]. In addition, a variety of curcumin analogues, including EF-24, C1206, C212, and DMC, have been shown to possess anti-leukemic properties in leukemia [244][245][246][247]. These results indicate that curcumin is a promising anti-cancer medicine against various subtypes of leukemia.…”