Therapeutic Effect of Quinacrine, an Antiprotozoan Drug, by Selective Suppression of p-CHK1/2 in p53-Negative Malignant Cancers

摘要

Quinacrine (QNC), antiprotozoan drug commonly used against Malaria and Giardiasis, has been recently tried for rheumatics and prion diseases via drug repositioning. In addition, several reports suggest antitumor effects of QNC through suppression of NF-kappa B and activation of p53. This study demonstrates the anticancer effect of QNC via a novel pathway through the elimination of checkpoint kinase 1/2 (Chk1/2) under p53-in-activated conditions. Inhibition of p53 by PFT-alpha or siRNA promotes QNC-induced apoptosis in normal fibroblast and p53-intact cancer cells. Considering that Chk1/2 kinases exert an essential role in the control of cell cycle, inhibition of Chk1/2 byQNC may induce cell death via uncontrolled cell cycle progression. Indeed, QNC reduces Chk1/2 expression under p53-impaired cancer cells and induces cell death in the G(2)-M phase. QNC increases the binding between p-Chk1/2 and beta-TrCP and promotes proteasome-dependent degradation. Moreover, QNC treatment displayed antitumor effects in a Villin-Cre; p53(+/LSL-R172H) intestinal cancer mouse model system as well as HCT116 p53(-/-) xenografts. (C) 2018 AACR.