Cytotoxicity Mechanism of Two Naphthoquinones (Menadione and Plumbagin) in Saccharomyces cerevisiae

Abstract

BackgroundQuinones are compounds extensively used in studies of oxidative stress due to their role in plants as chemicals for defense. These compounds are of great interest for pharmacologists and scientists, in general, because several cancer chemotherapeutic agents contain the quinone nucleus. However, due to differences in structures and diverse pharmacological effects, the exact toxicity mechanisms exerted by quinones are far from elucidatation.Methodology/Principal FindingsUsing Saccharomyces cerevisiae, we evaluated the main mechanisms of toxicity of two naphthoquinones, menadione and plumbagin, by determining tolerance and oxidative stress biomarkers such as GSH and GSSG, lipid peroxidation levels, as well as aconitase activity. The importance of glutathione transferases (GST) in quinone detoxification was also addressed. The GSSG/GSH ratio showed that menadione seemed to exert its toxicity mainly through the generation of ROS while plumbagin acted as an electrophile reacting with GSH. However, the results showed that, even by different pathways, both drugs were capable of generating oxidative stress through their toxic effects. Our results showed that the control strain, BY4741, and the glutathione transferase deficient strains (gtt1Δ and gtt2Δ) were sensitive to both compounds. With respect to the role of GST isoforms in cellular protection against quinone toxicity, we observed that the Gtt2 deficient strain was unable to overcome lipid peroxidation, even after a plumbagin pre-treatment, indicating that this treatment did not improve tolerance when compared with the wild type strain. Cross-tolerance experiments confirmed distinct cytotoxicity mechanisms for these naphthoquinones since only a pre-treatment with menadione was able to induce acquisition of tolerance against stress with plumbagin.Conclusions/SignificanceThese results suggest different responses to menadione and plumbagin which could be due to the fact that these compounds use different mechanisms to exert their toxicity. In addition, the Gtt2 isoform seemed to act as a general protective factor involved in quinone detoxification.

Plumbagin enhances TRAIL-induced apoptosis of human leukemic Kasumi-1 cells through upregulation of TRAIL death receptor expression, activation of caspase-8 and inhibition of cFLIP

“…Previous studies reported that plumbagin regulates the cellular redox state by modulation of GSH (36,39). In this study, we observed the content of GSH in Kasumi-1 cells treated by plumbagin for 6 and 12 h. The content of GSH was significantly decreased in groups of plumbagin treatment.…”

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

“…These QM intermediates react preferentially with GSH, leading to GSH depletion, which can cause death of both tumorigenic cells, as well as normal cells, depending on the cell lines. The QMs derived from naphthoquinones drugs (29-32 and 51) promote oxidative stress by a nucleophilic attack on GSH, as do also other quinoid compounds, such as menadione and plumbagine [98]. This has also been demonstrated with "simpler" derivatives of naphthoquinones, produced by photochemical reactions (83 and 86, see Fig.…”

Sources, Formation, Reactivity and Determination of Quinones in the Atmosphere

“…21 Assim, quinonas e seus produtos de redução (semiquinonas e hidroquinonas) são de interesse toxicológico devido à sua habilidade para gerar ERO [ânions radicais superóxidos (O 2 -), radicais hidroxila (·OH), peróxido de hidrogênio (H 2 O 2 ) e oxigênio singlete ( 1 O 2 )], as quais podem causar danos em membranas, proteínas e no DNA, podendo induzir a apoptose e, entre outros, a carcinogenese. 9,11,12 Relatos de experiências in vivo, 11,22 por exemplo, têm provado a natureza carcinogênica dessas substâncias sob determinadas condições. Em função disso, as quinonas são associadas com a incidência de vários tipos de câncer em humanos.…”

“…[1][2][3][4][5] Vários estudos demonstram os efeitos tóxicos e deletérios de quinonas para o organismo humano (indutor de várias doenças tais como câncer de pulmão, asma e inflamação alérgica), podendo também atuar como inibidora de enzimas importantes em sistemas celulares reparadores, causarem danos genéticos etc. [5][6][7][8][9][10][11] Por outro lado, as quinonas apresentam interesses toxicológicos e farmacoló-gicos consideráveis. 12,13 Estudos revelam variadas biodinamicidades, destacando-se, dentre muitas, a participação em processos bioquími-cos vitais, 6,14,15 a sua produção por insetos e vegetais como defesa química 16,17 além de atuarem como microbicidas, anticancerígenos e antiangiogênicos (Figura 1).…”

“…12,13 Estudos revelam variadas biodinamicidades, destacando-se, dentre muitas, a participação em processos bioquími-cos vitais, 6,14,15 a sua produção por insetos e vegetais como defesa química 16,17 além de atuarem como microbicidas, anticancerígenos e antiangiogênicos (Figura 1). 9,14 A Figura 1 é uma representação esquemática global sobre: (i) as principais fontes de quinonas emitidos para a atmosfera; (ii) seus caminhos e transformações químicas na atmosfera, iii) condições e propriedades físico-químicas que influenciam na distribuição entre as fases vapor, particulada e neblina (gotículas de água suspensa na atmosfera); e iv) efeitos sobre a saúde humana. 16 …”