Quinacrine has been widely explored in treatment of malaria, giardiasis, and rheumatic diseases. We find that quinacrine stabilizes p53 and induces p53-dependent and independent tumor cell death. Structurally, quinacrine bears similar characteristics with DNA-intercalating agents. Indeed, quinacrine competes with Propidium Iodide and shows a high binding affinity to DNA. Interestingly, quinacrine is a fluorescent dye that can be visualized under a laser microscope. In live cells, quinacrine is mainly clustered in the cytoplasm with a faint fluorescent signal in the nucleus. If the cells are fixed with methanol, quinacrine accumulates predominantly in the nucleus. Treatment by quinacrine alone at concentrations of 10-20 μM for 1-2 days can not kill hepatocellular carcinoma cells, such as HepG2, Hep3B, Huh7, which are also resistant to TRAIL. However, quinacrine renders these cells sensitive to treatment of TRAIL significantly. Co-treatment of these cells with quinacrine and TRAIL induces overwhelming cell death in 3-4 hr. Western blotting shows the level of DR5, a pro-apoptotic death receptor of TRAIL, is increased while MCL-1, a member of the Bcl-2 family, is decreased. While the synergistic effect of quinacrine with TRAIL appears to be in part independent of p53, knockdown of p53 in HepG2 cells by siRNA results in more cell death after treatment by quinacrine and TRAIL. The mechanism of quinacrine sensitization of hepatocellular carcinoma cells and the potential for clinical application are being further explored.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 680.