Activity of CoII-Quinalizarin: A Novel Analogue of Anthracycline-Based Anticancer Agents Targets Human DNA Topoisomerase, Whereas Quinalizarin Itself Acts via Formation of Semiquinone on Acute Lymphoblastic Leukemia MOLT-4 and HCT 116 Cells.

Abstract

Quinalizarin (THAQ), a hydroxy-9,10-anthraquinone analogue of the family of anthracycline anticancer drugs and an inhibitor of protein kinase, was observed for its anticancer activity. Because apart from showing anticancer activity, anthracyclines and their analogues also show cardiotoxic side effects, believed to be addressed through metal complex formation; an effort was made to realize this by preparing a CoII complex of THAQ. The aim of this study was to find out if complex formation leads to a decrease in the generation of intermediates that are responsible for toxic side effects. However, because this also meant that efficacy on cancer cells would be compromised, studies were undertaken on two cancer cell lines, namely, acute lymphoblastic leukemia (ALL) MOLT-4 and HCT116 cells. The complex decreases the flow of electrons from NADH to molecular oxygen (O2) in the presence of NADH dehydrogenase forming less semiquinone than THAQ. It showed increased affinity toward DNA with binding constant values remaining constant over the physiological pH range unlike THAQ (for which decrease in binding constant values with increase in pH was observed). The complex is probably a human DNA topoisomerase I and human DNA topoisomerase II poison acting by stabilizing the covalent topoisomerase-cleaved DNA adduct, a phenomenon not observed for THAQ. Activity of the compounds on cancer cells suggests that THAQ was more effective on ALL MOLT-4 cells, whereas the complex performed better on HCT116 cells. Results suggest that the formation of semiquinone probably dominates the action because of THAQ, whereas the performance of the complex is attributed to increased DNA binding, inhibition of topoisomerase, and so forth. Inspite of a decrease in the generation of superoxide by the complex, it did not hamper efficacy on either cell line, probably compensated by improved DNA binding and inhibition of topoisomerase enzymes which are positive attributes of complex formation. A decrease in superoxide formation suggests that the complex could be less cardiotoxic, thus increasing its therapeutic index.