Gardenin B-induced cell death in human leukemia cells involves multiple caspases but is independent of the generation of reactive oxygen species

SAAVEDRA, ESTER; LORO, JUAN F.; GARCÍA, C.; DEL ROSARIO, HENOC; CIFUENTE, D.A.; QUINTANA, JOSÉ; CABRERA, JAVIER; PERDOMO, JUAN; TONN, C.E.; ESTEVEZ, FRANCISCO

CHEMICO-BIOLOGICAL INTERACTIONS

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2016 vol. p. 220 - 227

0009-2797

Flavonoids have attracted great interest due to their possible anticancer activities. Here we investigated the antiproliferative activity of the flavonoids isolated from Baccharis scandens against human leukemiacell lines and found that the methoxyflavonoid gardenin B was the most cytotoxic compound against HL-60 and U-937 cells, showing IC50 values between 1.6 and 3.0 mM, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. These effects on viabilitywere accompanied by the concentration- and time-dependent appearance of apoptosis as evidenced by DNA fragmentation, formation of apoptotic bodies and a sub-G1 ratio increase. Comparative studies with the best-studied bioflavonoid quercetin indicate that gardenin B is a more cytotoxic and more apoptoticinducer than quercetin. Cell death induced by gardenin B was associated with: (i) a significant induction of caspase-2, -3, -8 and -9 activities; (ii) cleavage of the initiator caspases (caspase-2, -8 and -9), of theexecutioner caspase-3, and of poly(ADP-ribose) polymerase; and (iii) a concentration-dependent reactive oxygen species generation. In conclusion, apoptosis induced by gardenin B is associated with activationof both the extrinsic and the intrinsic apoptotic pathways of cell death and occurs through a mechanism that is independent of the generation of reactive oxygen species.