Aminopyrimidoisoquinolinequinone (APIQ) redox cycling is potentiated by ascorbate and induces oxidative stress leading to necrotic-like cancer cell death

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dc.contributor.authorVasquez, David R.
dc.contributor.authorVerrax, Julien
dc.contributor.authorValderrama, Jaime A.
dc.contributor.authorBuc Calderon, Pedro
dc.date.accessioned2025-01-20T23:58:15Z
dc.date.available2025-01-20T23:58:15Z
dc.date.issued2012
dc.description.abstractSeveral phenylaminopyrimidoisoquinolinequinones (APIQs) were tested for their cytotoxicity against different cancer cell lines (K562, T24, HepG2) in the presence or absence of ascorbate. Ascorbate enhanced the toxic effects of quinones with first half-wave potential E-1/2(I) values in the range of -480 to -660 mV. Phenylaminoquinones that were unsubstituted at position 6 exhibited greater cytotoxic activity than did their 6-methyl-substituted analogues. Two groups of compounds were further selected, namely 8-10 and 20-22, to study the cellular mechanisms involved in quinone cytotoxicity. Indeed, these compounds have the same range of redox potentials but differed considerably in their capacity to induce cell death. In the presence of ascorbate, the cell demise induced by compounds 8-10 was not caspase-3 dependent, as shown by the lack of activation of caspase-3 and the absence of cleaved PARP fragments. In addition, an index of ER stress (eIF2 alpha phosphorylation) was activated by these compounds. Quinones 8-10 decreased the cellular capacity to reduce MTT dye and caused marked ATP depletion. Taken together, our results show that ascorbate enhances quinone redox-cycling and leads to ROS formation that inhibits cell proliferation and provokes caspase-independent cell death. Interestingly, we also observed that quinone 8 had a rather selective effect given that freshly isolated peripheral blood leukocytes from human healthy donors were more resistant than human leukemia K562 cells.
dc.fuente.origenWOS
dc.identifier.doi10.1007/s10637-011-9661-1
dc.identifier.eissn1573-0646
dc.identifier.issn0167-6997
dc.identifier.urihttps://doi.org/10.1007/s10637-011-9661-1
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/95239
dc.identifier.wosidWOS:000303878700015
dc.issue.numero3
dc.language.isoen
dc.pagina.final1011
dc.pagina.inicio1003
dc.revistaInvestigational new drugs
dc.rightsacceso restringido
dc.subjectCancer
dc.subjectCell death
dc.subjectOxidative stress
dc.subjectQuinones
dc.subjectRedox cycling
dc.subjectROS formation
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleAminopyrimidoisoquinolinequinone (APIQ) redox cycling is potentiated by ascorbate and induces oxidative stress leading to necrotic-like cancer cell death
dc.typeartículo
dc.volumen30
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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