Gardenin B-induced cell death in human leukemia cells involves multiple caspases but is independent of the generation of reactive oxygen species. (25th August 2016)

• Record Type: Journal Article
• Authors: Cabrera, Javier; Saavedra, Ester; del Rosario, Henoc; Perdomo, Juan; Loro, Juan F.; Cifuente, Diego A.; Tonn, Carlos E.; García, Celina; Quintana, José; Estévez, Francisco
• Is Part Of: Chemico-biological interactions. Volume 256(2016)
• Page Start: 220
• Page End: 227
• Publication Date: 2016-08-25
• Subjects: Apoptosis -- Baccharis scandens -- Caspases -- Cytotoxicity -- Flavonoids; DHE dihydroethidium -- H2-DCF-DA 2′, 7′-dichlorodihydrofluorescein diacetate -- IC50 50% inhibition of cell growth -- MTT 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide -- NAC N-acetyl-l-cysteine -- PARP poly(ADP-ribose) polymerase -- PI propidium iodide -- ROS reactive oxygen species; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2016.07.016
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: 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 leukemia cell 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 μM, but had no significant cytotoxic effects against quiescent or proliferating human peripheral blood mononuclear cells. These effects on viability were 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 apoptotic inducer 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 the executioner 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 activation of 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. Graphical abstract: Highlights: Gardenin B is a potent cytotoxic compound against HL-60 and U937 cells. Baccharis scandens and gardenin B may have therapeutic value. Gardenin B arrests cells in the G2 -M phase of cell cycle. Cell death caused by gardenin B involves multiple caspases and is ROS-independent. Gardenin B activates the extrinsic and the intrinsic apoptotic pathways of cell death.