Oxidative stress induction by (+)-cordiaquinone J triggers both mitochondria-dependent apoptosis and necrosis in leukemia cells

Abstract

(+)-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.

Traditional uses, phytochemistry and pharmacology of the medicinal species of the genusCordia(Boraginaceae)

“…[61,67,70] Cordiaquinone J was found to be active against HL-60 and SF-295 cells with 2.7 lm and 6.6 lm IC 50 value, respectively, when screened for cytotoxicity study. [71] Four meroterpenoid benzoquinones were found to be present in two Cordia species, that is (1aS*,1bS*, 7aS*,8aS*)-4,5-dimethoxy-1a,7a-dimethyl-1,1a,1b,2,7,7a,8, 8a-octahydrocyclopropa [3,4]cyclopenta[1,2-b]naphthalene-3,6-dione (31) and microphyllaquinone (34) in C. globosa, and globiferin (32) and globiferane (33) in C. globifera. [72,73] Compounds 31 and 34 were investigated for cytotoxicity study which showed a significant effect with IC 50 value of 1.2-5 lg/ml [72] (Table 2.1.2).…”

“…Antimicrobial Showed significant activity against S. aureus, S. epidermidis, Bacillus subtilis, P. aeruginosa, P. aeruginosa, E. coli, Shigella flexineri, C. albicans, C. tropicalis, C. tropicalis, C. krusei, C. krusei, C. guilliermondii and C. guilliermondii [92] 8,8 0 -dimethyl-4,5-dimethoxy-3 0 ,4 0 -methylenodioxy-7-oxo-2,7 0 cyclolignan Antimicrobial Showed significant activity against S. aureus, S. aureus, S. epidermidis, Bacillus subtilis, P. aeruginosa, P. aeruginosa, E. coli, Shigella flexineri, C. albicans, C. tropicalis, C. tropicalis, C. krusei, C. krusei, C. guilliermondii and C. guilliermondii [92] Cordiarimides A and B Antioxidant Showed significant antioxidant in xanthine/xanthine oxidase (XXO) assay and in HL-60 human promyelocytic leukaemia cells [37] Globiferin Antimycobacterial Active against Mycobacterium tuberculosis H 37 Ra with MIC value of 6.2 lg/ml [73] Cordiachrome C Antimycobacterial Active against Mycobacterium tuberculosis H 37 Ra with MIC value of 1.5 lg/ml [73] 1AS*,1bS*,7aS*,8aS*)- [72] Trypanocidal Active against epimastigote forms of Trypanosoma cruzi [46] Cordigone, cordigol, benzofuran III, benzofuran IV Antifungal Active against Cladosporium cucumerinum [103] (+)-Cordiaquinone J Cytotoxic Demonstrated cytotoxic effect with IC 50 value from 2.7 to 6.6 lM in the cell lines HL-60 and SF-295, respectively [71] Cordiaquinone E Antifungal and larvicidal Active against Cladosporium cucumerinum (MIC 3 lg/ml), Candida albicans (MIC 6 lg/ml) and against the larvae of Aedes aegypti (MIC 12.5 lg/ml) [67] Cordiaquinone G Antifungal Active against Cladosporium cucumerinum (MIC 3 lg/ml), Candida albicans (MIC 6 lg/ml) [67] Cordiaquinone F Antifungal and larvicidal Active against Cladosporium cucumerinum (MIC 1.5 lg/ml), Candida albicans (MIC 6 lg/ml) and against the larvae of Aedes aegypti (MIC 25 lg/ml) [67] jararacussu and phospholipase A2 homologs, that is bothropstoxins I and II, in mice. The extract and rosmarinic acid also showed significant antimyotoxic activity against snake venom and isolated toxins in mice.…”

The chemical and biological activities of quinones: overview and implications in analytical detection

“…Although their precise mechanism of action is not yet fully understood, it is suggested that their major target is DNA. While some interact with DNA by alkylation or intercalation, others induce double strand DNA breaks and both DNA topoisomerase I and II mediated DNA cleavage (Asche 2005;Cai et al 2007Cai et al , 2008Marinho-Filho et al 2010).…”

Potent antileukemic action of naphthoquinoidal compounds: evidence for an intrinsic death mechanism based on oxidative stress and inhibition of DNA repair

“…To assay internucleosomal DNA fragmentation, the cells were incubated at 37 °C for 30 min in the dark in a lysis solution containing 0.1% citrate, 0.1% Triton X-100 and 50 µg mL -1 PI, and the percentage of degraded DNA was determined according to the number of cells displaying subdiploid (sub-G o /G 1 ) DNA in relation to the total number of cells examined. 31 Transmembrane mitochondrial potential (DYm) was evaluated using Rho-123 incorporation according to the method described by Marinho-Filho et al 32 Rho-123 is a cell-permeable, cationic, fluorescent dye that is readily sequestered by active mitochondria without inducing cytotoxic effects. Fluorescence was measured, and the percentage of mitochondrial depolarization was determined.…”