Liu, B.; Shen, Y.; Huang, H.; Della Croce, K.; Wu, M.; Fan, Y.; Liu, Y.; Xu, J.; Yao, G. Curcumin Derivative C212 Inhibits Hsp90 and Eliminates Both Quiescent and Growing Leukemia Cells. Preprints2019, 2019110206. https://doi.org/10.20944/preprints201911.0206.v1
Liu, B., Shen, Y., Huang, H., Della Croce, K., Wu, M., Fan, Y., Liu, Y., Xu, J., & Yao, G. (2019). Curcumin Derivative C212 Inhibits Hsp90 and Eliminates Both Quiescent and Growing Leukemia Cells. Preprints. https://doi.org/10.20944/preprints201911.0206.v1
Liu, B., Jianhua Xu and Guang Yao. 2019 "Curcumin Derivative C212 Inhibits Hsp90 and Eliminates Both Quiescent and Growing Leukemia Cells" Preprints. https://doi.org/10.20944/preprints201911.0206.v1
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 therapeutic agents, however, are lacking in the clinic. Here we report that a 4-arylmethyl derivative of the natural anticancer compound curcumin demonstrates a dual effect in eliminating both growing and quiescent leukemia cells. This curcumin derivative, C212, on the one hand, inhibits growing leukemia cells at a higher efficacy than curcumin by inducing apoptosis and cell cycle arrest; it, on the other hand, kills quiescent leukemia cells that are resistant to conventional chemotherapy drugs. Furthermore, C212 drives leukemia cells into and kills them at deep quiescence, avoiding the potential risk associated with awaking therapy-resistant subpopulation of quiescent leukemia cells. 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. Further elucidating the molecular mechanisms underlying the dual function of C212 in eliminating both growing and quiescent leukemia cells will aid the development of novel therapies against leukemia relapse.
leukemia; relapse; quiescence; dormancy; curcumin derivative; Hsp90; apoptosis; protein aggregation
Medicine and Pharmacology, Pharmacology and Toxicology
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