Inhibition of human topoisomerase I and activation of caspase-3 by aza-angucyclinones and arylaminopyrimido[4,5-c]isoquinoline-7,10-quinones

Abstract

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-1CC (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 the treatment against cancer.

EGR1 decreases the malignancy of human non-small cell lung carcinoma by regulating KRT18 expression

“…In the present study, GADD45B demonstrated increased mRNA levels in the EGR1-overexpressing H1299 cells. Several anti-apoptotic proteins, such as SON28, PRKDC29, and TOP130, were also downregulated in the EGR1-overexpressing cells, and several apoptotic proteins, including KRT1831, NR4A132, and TGM233, were upregulated in the same group of cells.…”

Synthesis and Antitumor Evaluation of 6-Aryl-substituted benzo[j]phenanthridine- and Benzo[g]pyrimido[4,5-c]isoquinolinequinones

“…As part of a research program on the synthesis and antitumor evaluation of N -heterocyclic quinones we have described the synthesis and antitumor properties of benzo[ j ]phenanthridine- and benzo[ g ]-pyrimido[4,5- c ]isoquinolinequinone derivatives [ 14 ]. Recent evidences demonstrate that some members of these series have potential anti-cancer activity through inhibition of TOP1 catalytic activity and induction of apoptosis [ 15 ]. The synthesis of these tetracyclic quinones, such as 1 and 2 ( Figure 2 ), was accomplished by means a strategy involving the heterocyclization of acyl-1,4-benzoquinones with enaminones to construct the ABC-ring systems followed by a Diels-Alder reaction to assemble the D-benzene nucleus.…”

Synthesis of novel amidines via one-pot three component reactions: Selective topoisomerase I inhibitors with antiproliferative properties

“…Topoisomerase I inhibitors are a unique class of anticancer agents that cause cell death by interfering with DNA replication in cancer cells (Delgado et al, 2018). According to the literature, quinoline-based derivatives exhibited an antiproliferative impact by inhibiting variable proteins such as topo I and topo II (Monsalve et al, 2012;Ismail et al, 2013).…”