Potent cytotoxicity and inhibition of pan-cell cycle progression by Alchemix, a novel alkylating anthraquinone

Abstract

12030 Introduction: DNA topoisomerase II (topo II) is crucial to the maintenance of cancer cells in a proliferative state. DNA intercalation is a crucial part of topo II inhibition by DNA affinic anthraquinones. Potent cytotoxicity of anthraquinones, is related to their slow rate of dissociation from DNA, the kinetics of which favours long-term trapping of the topo-DNA complexes. Currently available DNA interacting agents at best promote a transient inhibition of topo II, since the topo-drug-DNA ternary complex is reversed by removal of the intracellular drug pool. Results: Alchemix cell cycle events: DNA content and Cyclin B1 expression were measured using flow cytometry and a p53 functional human osteosarcoma cell line (U2-OS) The results indicate: (ii) slow pan-cell cycle progression and mitotic commitment with a limited expression of G2 arrest, (iii) B1 cyclin tracking reveals that escape from Alchemix-induced cell cycle arrest in G2 is forcing some cells to enter polyploidy via an aberrant mitosis in keeping with topoisomerase II inhibition. Alchemix in vitro activity against the NCI human cell line panel including several drug resistant cancer cell lines had a mean IG50 = 49 nM. 11 of the 24 cell lines tested have an IG50 of <10 nM. Alchemix retains potent activity against chemotherapy resistant tumors including drug resistant ones. Conclusions: Alchemix possesses potent activity across a variety of different human tumors and significantly shows potent activity in cisplatin and anthracyline resistant human tumors Alchemix has pan-cell cycle effects. Multilevel targeting by Alchemix reduces the probability of evasion of cell cycle related pharmacodynamic responses. Results help explain the activity of Alchemix in both cisplatin and anthracycline resistant tumors in vitro and in vivo. [Table: see text]