Activity of Co^II–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 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 (O 2 ) 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.

Free radical induced activity of an anthracycline analogue and its MnII complex on biological targets through in situ electrochemical generation of semiquinone

“…One approach to modifying anthracyclines is through complex formation using bio-friendly metal ions [ 25 , 26 , 27 ]. Simpler analogues seeking to decrease the cost of such drugs have also been tried [ 17 , 18 , 19 , 20 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. While results vary, there are several issues before such simpler analogues could become drugs [ 17 , 18 , 19 , 20 , 28 , 29 , 30 , 33 , 34 , 35 ].…”

“…Simpler analogues seeking to decrease the cost of such drugs have also been tried [ 17 , 18 , 19 , 20 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. While results vary, there are several issues before such simpler analogues could become drugs [ 17 , 18 , 19 , 20 , 28 , 29 , 30 , 33 , 34 , 35 ]. Whether it be anthracyclines or its hydroxy-9,10-anthraquinone analogues, studies reveal intermediates like semiquinone radical anion [ 36 , 37 ] are an important component of drug action that are either moderately or significantly decreased following complex formation [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

“…While results vary, there are several issues before such simpler analogues could become drugs [ 17 , 18 , 19 , 20 , 28 , 29 , 30 , 33 , 34 , 35 ]. Whether it be anthracyclines or its hydroxy-9,10-anthraquinone analogues, studies reveal intermediates like semiquinone radical anion [ 36 , 37 ] are an important component of drug action that are either moderately or significantly decreased following complex formation [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Therefore, while complex formation could address cardiotoxic side effects, efficacy could be affected as well [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

“…Whether it be anthracyclines or its hydroxy-9,10-anthraquinone analogues, studies reveal intermediates like semiquinone radical anion [ 36 , 37 ] are an important component of drug action that are either moderately or significantly decreased following complex formation [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. Therefore, while complex formation could address cardiotoxic side effects, efficacy could be affected as well [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. In majority of cases however, it is seen that complexes are more effective ( in vitro ) than the parent molecule [ 26 , 28 , 30 , 32 , 33 , 34 , 35 ].…”

“…Therefore, while complex formation could address cardiotoxic side effects, efficacy could be affected as well [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. In majority of cases however, it is seen that complexes are more effective ( in vitro ) than the parent molecule [ 26 , 28 , 30 , 32 , 33 , 34 , 35 ]. This means in case of complexes, loss in efficacy owing to decreased formation of semiquinone is compensated by other attributes of complex formation [ 25 , 26 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”