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

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.