Activity of CoII–Quinalizarin: ANovel Analogue of Anthracycline-Based Anticancer Agents Targets HumanDNA Topoisomerase Whereas Quinalizarin Itself Acts via Formationof Semiquinone on Acute Lymphoblastic Leukemia MOLT-4 and HCT116 Cells

摘要

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 Co^II 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 (forwhich decrease in binding constant values with increase in pH wasobserved). The complex is probably a human DNA topoisomerase I andhuman DNA topoisomerase II poison acting by stabilizing the covalenttopoisomerase-cleaved DNA adduct, a phenomenon not observed for THAQ.Activity of the compounds on cancer cells suggests that THAQ was moreeffective on ALL MOLT-4 cells, whereas the complex performed betteron HCT116 cells. Results suggest that the formation of semiquinoneprobably dominates the action because of THAQ, whereas the performanceof the complex is attributed to increased DNA binding, inhibitionof topoisomerase, and so forth. Inspite of a decrease in the generationof superoxide by the complex, it did not hamper efficacy on eithercell line, probably compensated by improved DNA binding and inhibitionof topoisomerase enzymes which are positive attributes of complexformation. A decrease in superoxide formation suggests that the complexcould be less cardiotoxic, thus increasing its therapeutic index.