Please use this identifier to cite or link to this item: https://doi.org/10.1002/cmdc.201200293
Title: Curcumin Analogues with Potent and Selective Anti-proliferative Activity on Acute Promyelocytic Leukemia: Involvement of Accumulated Misfolded Nuclear Receptor Co-repressor (N-CoR) Protein as a Basis for Selective Activity
Authors: Tan, K.-L.
Koh, S.-B.
Ee, R.P.-L. 
Khan, M. 
Go, M.-L. 
Keywords: APL
Curcumin
Inhibitors
Leukemia
N-CoR
Protein folding
Issue Date: Sep-2012
Citation: Tan, K.-L., Koh, S.-B., Ee, R.P.-L., Khan, M., Go, M.-L. (2012-09). Curcumin Analogues with Potent and Selective Anti-proliferative Activity on Acute Promyelocytic Leukemia: Involvement of Accumulated Misfolded Nuclear Receptor Co-repressor (N-CoR) Protein as a Basis for Selective Activity. ChemMedChem 7 (9) : 1567-1579. ScholarBank@NUS Repository. https://doi.org/10.1002/cmdc.201200293
Abstract: Curcumin arrests the proliferation of acute promyelocytic leukemia (APL) cells by stabilizing the misfolded nuclear receptor co-repressor (N-CoR) protein, thereby sensitizing APL cells to apoptosis induced by the unfolded protein response. This phenomenon was attributed to inhibition of the proteasomal and protease-induced breakdown of misfolded N-CoR by curcumin. Curcumin is, however, a modest inhibitor and affected the viability of APL cells at micromolar concentrations. Modifying curcumin at its conjugated β-diketone linker and terminal phenyl rings yielded potent congeners with sub-micromolar growth inhibitory activities which selectively kill APL cells over non-APL leukemic and nonmalignant cells. Analogues with pronounced APL-selective anti-proliferative activities, as observed in representative dibenzylidenecyclohexanones and dibenzylidenecyclopentanones, strongly promoted the accumulation of misfolded and nonfunctional N-CoR at significantly lower concentrations than their growth inhibitory IC50 values. These compounds also inhibited the human 20S proteasome in an enzyme-based assay, thus providing convincing support for the prevailing hypothesis that impeding the degradation of N-CoR is a key mechanistic event contributing to APL cell death. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Source Title: ChemMedChem
URI: http://scholarbank.nus.edu.sg/handle/10635/110729
ISSN: 18607179
DOI: 10.1002/cmdc.201200293
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