Abstract 5478: A novel chloroquine derivative inhibits proteasome function, deregulates centrosome cycle and has selective anti-tumor activity

Abstract

Abstract The use of chloroquine as a lead compound in anticancer drug discovery is being widely explored because of its low toxicity and ability to sensitize cancer cell killing when used in combination with radiotherapy. Therefore we designed and screened chloroquine analogs using hybrid pharmacophore approach. We report here anti-cancer activity and characterization of a novel anti-cancer compound VR23 derived from chloroquine. Biological investigation revealed that the derivative VR23 inhibits proteasome function, selectively kills cancer cells, causes the formation of supernumerary centrosomes, tri- and multi-polar mitosis, and slows down the progression of cells through cell cycle. In addition VR23 has shown promising anti-cancer activity in animal work. Further, proteasome inhibition deregulates the translocation of cyclin E and other centrosomal proteins including plk4 and plk1 on centrosomes. This, in turn, leads to formation of supernumerary centrosomes, mitotic catastrophe, p38 stress kinase mediated activation of apoptosis, and eventually cancer cell death. The work elucidates the consequences of the use of proteasome inhibitor on centrosome duplication cycle which, in turns also delays cell cycle progression and leads to the formation of irregular microtubule asters. Interestingly such phenotype was absent from non-malignant cell line. Citation Format: Sheetal Pundir. A novel chloroquine derivative inhibits proteasome function, deregulates centrosome cycle and has selective anti-tumor activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5478. doi:10.1158/1538-7445.AM2014-5478