Oxidative stress induction by (+)-cordiaquinone J triggers both mitochondria-dependent apoptosis and necrosis in leukemia cells.
(+)-Cordiaquinone J is a 1,4-naphthoquinone isolated from the roots of Cordia leucocephala that has antifungal and larvicidal effects. However, the cytotoxic effects of (+)-cordiaquinone J have never being explored. In the present study, the effect of (+)-cordiaquinone J on tumor cells viability was investigated, showing IC(50) values in the range of 2.7-6.6muM in HL-60 and SF-295 cells, respectively. Studies performed in HL-60 leukemia cells indicated that (+)-cordiaquinone J (1.5 and 3.0muM) reduces cell viability and 5-bromo-2-deoxyuridine incorporation after 24h of incubation. (+)-Cordiaquinone J showed rapid induction of apoptosis, as indicated by phosphatidylserine externalization, caspase activation, DNA fragmentation, morphologic changes, and rapid induction of necrosis, as indicated by the loss of membrane integrity and morphologic changes. (+)-Cordiaquinone J altered the redox potential of cells by inducing the depletion of reduced GSH intracellular content, the generation of reactive oxygen species and the loss of mitochondrial membrane potential. However, pre-treatment of cells with N-acetyl-l-cysteine abolished most of the observed effects related to (+)-cordiaquinone J treatment, including those involving apoptosis and necrosis induction.
Marinho-Filho
José Delano B
JD
Departamento de Fisiologia e Farmacologia, Faculdade de Medicina, Universidade Federal do Ceará, Rua Cel. Nunes de Melo 1127, Fortaleza, Ceará, Brazil.
Bezerra
Daniel P
DP
Araújo
Ana J
AJ
Montenegro
Raquel C
RC
Pessoa
Claudia
C
Diniz
Jaécio C
JC
Viana
Francisco A
FA
Pessoa
Otília D L
OD
Silveira
Edilberto R
ER
de Moraes
Manoel O
MO
Costa-Lotufo
Letícia V
LV
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D031213:Cordia / Q000737:chemistry; D005978:Glutathione / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009285:Naphthoquinones / Q000302:isolation & purification / Q000627:therapeutic use / Q000633:toxicity*; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects*; D018517:Plant Roots / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism
D009285:Naphthoquinones; D017382:Reactive Oxygen Species; C411134:cordiaquinone J; D053148:Caspase 3; D053179:Caspase 7; D005978:Glutathione