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.
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 IC(50)  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.
Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Kheng-Lin
KL
Tan
Siang-Boon
SB
Koh
Rachel Pui-Lai
RP
Ee
Matiullah
M
Khan
Mei-Lin
ML
Go
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D056970:Co-Repressor Proteins / Q000032:analysis / Q000378:metabolism*; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects
D000970:Antineoplastic Agents; D056970:Co-Repressor Proteins; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin