Inhibition of human topoisomerase I and activation of caspase-3 by aza-angucyclinones and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones
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Date
2012
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Publisher
SPANDIDOS PUBL LTD
Abstract
Cancer is the second cause of death in the world after cardiovascular diseases. Cancer cells acquire capacities not present in normal cells, such as self-sufficiency, resistance to antiproliferative stimuli, evasion of apoptosis, unlimited replication, invasiveness and metastasis. Consequently, it is of major interest to explore and develop molecules with anticancer activity directed to specific targets. In this study, we aimed to evaluate two series of polycyclic quinones: aza-angucyclinone and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones, in their capacity to inhibit human topoisomerase I (TOP1) and to trigger apoptosis through activation of caspase-3. We evaluated the capacity of the two series of polycyclic quinones to inhibit TOP1, using a DNA supercoiled relaxation assay and their capacity to induce apoptosis through the activation of caspase-3 in HL60 cells. Both series of quinones inhibited TOP1 activity over 50%. When we evaluated the pro-apoptotic capacity of both series of quinones, at therapeutically relevant concentrations, the arylaminoquinones ADPA-ICC (methyl 7-(4-methoxyphenyl)amino-1,3-dimethyl-5,8-dioxo-5,8-dihydroisoquinoline-4-carboxylate), P4 (9-phenylamino-3,4-dihydrophenanthridine-1,7,10(2H)-trione) and the aza-angucyclinone OH-6H (8-hydroxy-2,4-dimethyl-2H,4H-benzo[g]pyrimido[4,5-c]isoquinoline-1,3,7,12-tetraone) increased the caspase-3 activity by approximately 2-fold over the control. The series of the arylaminoquinones and aza-angucyclinones showed differential antiproliferative capacity. We further identified a group of them that showed antiproliferative capacity possibly through inhibition of TOP1 and by activation of caspase-3. This group of molecules may represent a potential pharmacological tool in treatment against cancer.
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Keywords
topoisomerase 1, quinones, chemotherapeutic, inhibitor, caspase-3, TRIPTYCENE BISQUINONES, CANCER CELLS, APOPTOSIS, CAMPTOTHECIN, QUINONES, VITRO