Wild type strain (WT) and YDL100c disrupted strain (KO) were grown at 30oC for 8 hr after adding 50 £gM menadione. Cells of both strains were assayed for trehalose accumulation, intracellular molecular oxidation level, membrane lipid oxidation, and glutathione (GSH) content. The data showed both the molecular and membrane lipid oxidation levels are higher and the GSH content is lower in KO compared with WT in the presence of menadione. The catalase activity in KO strain are reduced than that in WT strain, catalase activity would affect in the presence of menadione. Further study of antioxidant gene expressions showed that TPS1 and CTT1 were involved in the general stress response¡FSOD1, GSH1, TRR1 and TRX2 were involved in the specific stress response. Above mentioned mRNA level were reduced, suggesting that the deletion of YDL100c in S. cerevisiae affects the operation of general and specific stress response when grown in the presence of menadione.

The crystalline lens is a unique cellular organ that performs metabolic processes while maintaining optical functionality. Mitochondria play a vital role in providing the cell with the energy necessary for these metabolic processes and have recently been shown to be more metabolically active than previously thought. To test the hypothesis that mitochondrial function directly influences the optical function of the lens, bovine lenses were treated with 50 μM, 200 μM, 600 μM and 1000 μM menadione, a mitochondrial specific toxin that renders the mitochondria inactive, and the Back Vertex Distance (BVD) variability was observed over 216 hours. Confocal micrographs of secondary fibre cells’ mitochondria were also analyzed for 50 μM, 200 μM, and 600 μM menadione treatment over 48 hours. Increase in BVD variability (± s.e.m.) was observed within 24 hours from 0.28 ± 0.021 to 1.83 ± 0.75 for the 600 μM treated lenses. Confocal micrograph analysis showed a trend toward a decrease in the average length of mitochondria from 7.9 ± 0.8 to 3.7 ± 0.9 over for 200 μM treated lenses and from 5.9 ± 1.0 to 3.6 ± 0.6 for the 600 μM treated lenses over 48 hours. These data show that indeed menadione has a detrimental effect on mitochondria as a function of both time and concentration and this change in mitochondria precedes changes in BVD variability directly linking mitochondrial function to optical function.

The crystalline lens is a unique cellular organ that performs metabolic processes while maintaining optical functionality. Mitochondria play a vital role in providing the cell with the energy necessary for these metabolic processes and have recently been shown to be more metabolically active than previously thought. To test the hypothesis that mitochondrial function directly influences the optical function of the lens, bovine lenses were treated with 50 μM, 200 μM, 600 μM and 1000 μM menadione, a mitochondrial specific toxin that renders the mitochondria inactive, and the Back Vertex Distance (BVD) variability was observed over 216 hours. Confocal micrographs of secondary fibre cells’ mitochondria were also analyzed for 50 μM, 200 μM, and 600 μM menadione treatment over 48 hours. Increase in BVD variability (± s.e.m.) was observed within 24 hours from 0.28 ± 0.021 to 1.83 ± 0.75 for the 600 μM treated lenses. Confocal micrograph analysis showed a trend toward a decrease in the average length of mitochondria from 7.9 ± 0.8 to 3.7 ± 0.9 over for 200 μM treated lenses and from 5.9 ± 1.0 to 3.6 ± 0.6 for the 600 μM treated lenses over 48 hours. These data show that indeed menadione has a detrimental effect on mitochondria as a function of both time and concentration and this change in mitochondria precedes changes in BVD variability directly linking mitochondrial function to optical function.

yes / Superoxide anions have been associated with many aspects of cardiovascular disease. Menadione is a superoxide anion donor that alters the heart’s electrical and mechanical functions. The aim of this study was to demonstrate simultaneous changes in intracellular Ca2+ ([Ca2+]i) and mechanical activity in intact adult cardiac myocytes, and mechanical activity and electrical activity in isolated whole hearts in order to provide greater insight into the mechanisms associated with the detrimental effects of menadione on the myocardium. Isolated hearts from adult male Wistar rats (n = 11, 200–250 g) were Langendorff perfused at 38°C with a Krebs–Henseleit solution. A saline-filled balloon was placed in the left ventricle (LV) in order to measure diastolic and developed pressure. Monophasic action potentials were simultaneously recorded from the epicardial surface. External stimulation at 5 Hz and intrinsic pacing were used throughout a 10 min control period and 30 min exposure to 50 μM menadione. Single LV myocytes (n = 7 from n = 4 animals) were loaded with the Ca2+-indicator Fura4-AM, stimulated at 1 Hz and exposed to 50 μM menadione. Myocyte length was simultaneously measured with [Ca2+]i using a video edge detection system. In isolated hearts, exposure to menadione significantly decreased contractility and action potential duration (with a similar time course); intrinsic heart rate and rhythmicity. Diastolic pressure was significantly increased. In single adult myocytes, menadione caused a significant increase in diastolic [Ca2+]i and a decrease in resting cell length and led to spontaneous release of [Ca2+]i. We conclude that the effects of menadione upon electrical and mechanical activity of the heart are at least in part a consequence of dysregulation of [Ca2+]i handling and the subsequent increase in diastolic [Ca2+] alterations in [Ca2+]i are consistent with the generation of delayed after depolarization arrhythmias.

As intestinal epithelial cells mature, they continuously transition from proliferation to differentiation to apoptosis under the influence of cell signalling pathways including c-Jun N-terminal kinase (JNK). Glutathione S-transferases (GSTs) are cytoprotective detoxification enzymes, some of which, including GSTA1, also sequester and inhibit JNK through complex formation. Thus, GSTA1 may be a key sensor of cellular state and regulator of responses to cell stress stimuli. The focus of this research study was to investigate the functional importance of GSTA1 in two contexts: 1) modulating complex integrity with JNK and activation of JNK by oxidative stress, 2) controlling cellular transitioning between proliferation, differentiation and apoptosis. In the first study, the impact of GSTA1 levels on dissociation of GSTA1-JNK complexes and JNK activation in response to cellular stress was investigated in the human colonic adenocarinoma Caco-2 cells. The pro-oxidant menadione caused GSTA1-JNK complex dissociation in preconfluent Caco-2 cells, whereas postconfluent cells were relatively resistant to this effect. Preconfluent cells were more sensitive than postconfluent cells to menadione-induced cytotoxicity. Additionally, menadione-induced JNK activation was transient since removal of the stimulus resulted in re-association of GSTA1 with JNK and significantly reduced cytotoxicity. Over-expression and knockdown of GSTA1 affected the degree of GSTA1-JNK complex association without altering the JNK activation. However, enhanced GSH levels by N-acetyl cysteine blocked menadione-induced complex dissociation and JNK activation in Caco-2 cells. The results suggest that the mechanism of menadione-mediated JNK activation involves the production of reactive oxygen species, likely superoxide anion, and that the level of intracellular GSH plays an important role in preventing menadione-induced GSTA1-JNK complex dissociation and subsequent JNK activation. The functional importance of GSTA1 in controlling cellular proliferation, differentiation and apoptosis was investigated. Sodium butyrate (NaB) is a short-chain fatty acid, physiologically present in the human large intestine and modulates transitioning of cell states in colon cancer cell lines. GSTA1 levels increased in association with differentiation markers in postconfluent Caco-2 cells. Forced expression of GSTA1 significantly reduced cellular proliferation and siRNA-mediated down-regulation of GSTA1 significantly increased cells in S-phase and associated cell proliferation. NaB (1 mM) reduced Caco-2 cell proliferation, increased differentiation and up-regulated GSTA1 activity. In contrast, higher dose of NaB (10 mM) caused toxicity in preconfluent cells via apoptosis through caspase-3 activation in association with reduced GSTA1 activity. GSTA1 down-regulation by siRNA did not alter NaB-induced differentiation or the sensitivity of Caco-2 cells to NaB-induced apoptosis. Furthermore, NaB (10 mM) caused GSTA1-JNK complex dissociation but did not affect JNK activation. These findings suggest that GSTA1 levels may play a role in modulating enterocyte proliferation but do not influence differentiation or apoptosis.

No description available.

Thesis (MScEng (Process Engineering))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Partially oxygenated aromatic compounds, e.g. quinones, hydroquinones and cresols, play a vital role in the fine chemical industry and were initially prepared by stoichiometric oxidation processes that produce toxic products that are hazardous towards the environment. As a result, it was important to investigate environmentally friendly processes for the hydroxylation of aromatic compounds. This resulted in newer methods using Ti-substituted microporous zeolites as catalysts with hydrogen peroxide as oxidant in the presence of a solvent. However, the methods were found to be ineffective for large, bulky substrates due to the small pore structure. This led to using Ti-mesoporous materials as catalysts but suffered from two drawbacks; the hydrophilic nature and low hydrothermal stability of the catalyst structure. Ti-microporous and Ti-mesoporous materials acting as catalysts for the oxidation of bulky substrates achieved environmentally friendly processes but obtained low conversions and quinone yields. Therefore, the challenge has been to develop a process that is environmentally friendly, achieves high conversions, where the catalyst acts truly heterogeneous and obtains high quinone yields for the hydroxylation of bulky substrates. Recently, micropores/mesopores catalysts incorporating advantages of both micropores and mesopores materials were synthesised and seemed promising for the hydroxylation of bulky substrates. This study focuses on synthesising and evaluating the feasibility of various Ti-substituted catalysts for improving the hydroxylation of the bulky substrate, 2-methylnaphthalene (2MN) with hydrogen peroxide as oxidant in the presence of a solvent, acetonitrile. The oxidation of 2MN produces 2-methyl-1,4-naphthoquinone (2MNQ). 2MNQ is also known as menadione or Vitamin K3 and acts as a blood coagulating agent. The catalysts synthesised for this study were mesoporous catalysts, Ti- MCM-41 and Ti-MMM-2 and microporous/mesoporous catalysts, Ti-MMM-2(P123) and a highly ordered mesoporous material. The main objective of this study was to design an efficient process that is environmentally friendly and achieves high 2MN conversions and 2MNQ yields. This was achieved by evaluating the various catalysts synthesised, reaction conditions, testing if the catalyst was truly heterogeneous and identifying the products formed from the process. The designed process was proved to be environmentally friendly because the system did not produce products that were harmful towards the environment. The products identified in this study were 2MNQ, 2-methyl-1-naphthol, 2-naphthaldehyde, 3-ethoxy-4-methoxybenzaldehyde and menadione epoxide. An investigation was conducted to determine which catalyst synthesised favoured this process by quantifying the effect reaction conditions have on the various catalysts. The reaction conditions were defined in terms of the hydrogen peroxide volume, catalyst amount, solvent volume, substrate amount, reaction time and reaction temperature. The desired catalyst for this study obtained the highest 2MN conversions in comparison with the other catalysts and favoured the formation of 2MNQ. The catalyst achieving the highest conversions and favouring 2MNQ in most cases for this investigation was the highly ordered mesoporous material. Improving operating conditions to obtain high 2MNQ yields for the oxidation of 2MN to 2MNQ over the highly ordered mesoporous material was determined by varying the reaction conditions with the one factor at a time approach and a factorial design. The one factor at a time approach showed that best 2MNQ yields were obtained at 1 g substrate when investigating a change in substrate amount between 0.5 g and 2 g. Best 2MNQ yields were obtained at 10 ml solvent when investigating a change of solvent volume between 5 ml and 20 ml. The 2MNQ yield increased with increasing the catalyst amount (50 mg to 200 mg), hydrogen peroxide volume (1 ml to 6 ml) and increasing the reaction times (2 hour to 6 hours) at reaction temperatures, 120°C and 150°C. The yield decreased with increasing the reaction time (2 hours to 6 hours) at reaction temperature, 180°C. A preliminary 2 level factorial design was prepared to observe if there were any important interactions affecting the 2MNQ yield. The results from the factorial design indicated that the hydrogen peroxide volume had the most influence on the 2MNQ yield followed by the reaction time-reaction temperature interaction and reaction temperature. From the factorial design, the yield increased by increasing the hydrogen peroxide volume and reaction temperature whilst decreasing the reaction temperature-reaction time interaction. The highest 2MNQ yields and 2MN conversions obtained for the hydroxylation of 2MN to 2MNQ over the highly ordered mesoporous material in this study were in the ranges 48-50 % and 97-99 %, respectively. This study indicates that the process system, reaction conditions and catalyst type have an impact on the products formed, 2MN conversion, 2MNQ selectivity and 2MNQ yield. The highly ordered mesoporous material was found to be truly heterogeneous because no leaching occurred and the catalyst could be recycled without losing its catalytic activity and selectivity for at least two catalyst cycles. It can be concluded that the highly ordered mesoporous material is therefore a promising catalyst for the selective oxidation of bulky substrates with aqueous H2O2 because it produces an environmentally friendly process, achieves high conversions, obtains high quinone yields and the catalyst truly acts heterogeneous. / AFRIKAANSE OPSOMMING: Gedeeltelik geoksideerde aromatiese verbindings (bv. kinone, hidrokinone en kresole) speel ‘n belangrike rol in die fynchemiebedryf. Hierdie verbindings is aanvanklik voorberei deur stoïchiometriese oksidasie prosesse wat gifstowwe nadelig vir die omgewing veroorsaak. Daarom is dit belangrik om omgewingsvriendelike prosesse vir die hidroksilering van aromatiese verbindings te ondersoek. Hierdie ondersoeke het gelei tot nuwe metodes wat Ti-vervangde mikroporeuse seoliete as katalisator met waterstofperoksied as oksideermiddel in die teenwoordigheid van ʼn oplosmiddel benut. Dit is egter gevind dat hierdie metodes oneffektief is vir groot, lywige substrate weens die fyn poriestruktuur van die katalisator. Dit lei tot die gebruik van Ti-mesoporeuse materiale as katalisators, maar toon twee tekortkominge, naamlik die hidrofiliese aard en lae hidrotermiese stabiliteit van die katalisatorstruktuur. Ti-mikroporeuse en Ti-mesoporeuse materiale benut as katalisators vir die oksidasie van lywige substrate lewer omgewingsvriendelike prosesse, maar vermag lae omsetting en kinoonopbrengs. ʼn Uitdaging is dus om ʼn omgewingsvriendelike proses te ontwikkel met hoë omsetting, waar die katalisator werklik heterogeen optree en hoë kinoonopbrengs lewer vir die hidroksilering van lywige substrate. Katalisators vir die hidroksilering van lywige substrate wat die voordele van beide mikroporieë/mesoporieë ten toon stel is onlangs gesintetiseer, met belowende resultate. Hierdie studie is ingestel op die sintetisering en evaluering van uitvoerbaarheid van verskeie Tivervangde katalisators vir die optimering van die hidroksilering van die lywige substraat, 2- metielnaftaleen (2MN), met waterstofperoksied as oksideermiddel met asetonitriel as oplosmiddel. Die oksidering van 2MN produseer 2-metiel-1,4-naftokinoon (2MNK), ook bekend as vitamien K3, ʼn bloedstollingsmiddel. Die katalisators vervaardig vir hierdie studie was die mesoporeuse katalisators, Ti-MCM-41 en Ti-MMM-2, en die mikroporeuse/mesoporeuse katalisor Ti-MMM-2(P123), sowel as ʼn hoogs geordende mesoporeuse materiaal. Die hoofdoel van hierdie studie was om ʼn doeltreffende, omgewingsvriendelike proses met hoë 2MN omsetting en 2MNK opbrengs te ontwerp. Voorgenoemde is vermag deur verskeie gesintetiseerde katalisators en reaksiekondisies te evalueer, om te toets of katalisators werklik heterogeen is, en om die prosesprodukte te identifiseer. Die ontwerpte proses kan beskou word as omgewingsvriendelik, aangesien die stelsel geen produkte lewer wat skade aan die natuur kan veroorsaak nie. 2MNK, 2-metiel-1-naftol, 2-naftaldehied, 3- etoksi-4-metoksibensaldehied en menadioonepoksied is in hierdie studie geïdentifiseer as prosesprodukte. Om te bepaal watter gesintetiseerde katalisators hierdie proses begunstig, is ʼn ondersoek geloods om die effek van reaksiekondisies op die verskeie katalisators te kwantifiseer. Die reaksiekondisies is omskryf in terme van waterstofperoksiedkonsentrasie, katalisatorhoeveelheid, oplosmiddelvolume, substraathoeveelheid, reaksietyd en reaksietemperatuur. Die gewenste katalistor vir hierdie proses was die katalisator wat die hoogste 2MN omsetting lewer en die vorming van 2MNK bevorder. Die hoogs geordende mesoporeuse materiaal was in hierdie ondersoek die katalisator met die hoogste omsetting wat ook 2MNK-vorming bevorder het in die meeste gevalle. Om die beste bedryfstoestande vir hoë 2MNK opbrengs vanaf die oksidering van 2MN oor hoogs geordende mesoporeuse materiaal te bepaal, is die reaksiekondisies verander deur met een faktor op ʼn slag te verander, sowel as faktorverandering volgens ʼn faktoriaalontwerp. Die een-faktor-op-‘nslag benadering het getoon dat die 2MNK opbrengs ʼn maksimum bereik waar die substraathoeveelheid tussen 0.5 g en 2 g wissel, met die oplosmiddelvolume tussen 5 ml en 20 ml. Die opbrengs het ietwat verbeter met ʼn groter hoeveelheid katalisatorhoeveelheid (van 50 mg na 200 mg), terwyl die opbrengs drasties verbeter het waar die waterstofperoksiedvolume van 3 ml tot 6 ml verhoog is. Die opbrengs het ook verbeter met ʼn styging in reaksietemperatuur (van 120°C tot 180°C) met reaksietydintervalle van 1 tot 6 ure. Die opbrengs het egter gedaal by 180°C waar reaksietye langer as 2 ure. Volgens die resultate van die een-faktor-op-‘n-slag benadering blyk dit dat reaksietemperatuur, waterstofperoksiedvolume, katalisatorhoeveelheid en reaksietyd faktore is wat verhoogde 2MNK opbrengs bevorder. Hierdie reaksiekondisies is geselekteer vir die faktoriaalontwerp. ʼn Voorlopige 2- vlak faktoriaalontwerp is voorberei om te bepaal of daar enige belangrike interaksies is wat die 2MNK opbrengs beïnvloed. Die resultate van die faktoriaalontwerp het aangetoon dat waterstofperoksiedvolume die grootste invloed op 2MNK opbrengs het, gevolg deur die interaksie van reaksietyd en reaksietemperatuur, en dan reaksietemperatuur. Die faktoriaalontwerp resultate toon verder dat opbrengs verhoog met toenemende waterstofperoksiedvolume en reaksietemperatuur, terwyl die opbrengs verlaag soos wat die reaksietyd-reaksietemperatuur interaksie toeneem. Hierdie studie het hoogste 2MNK opbrengs van 48-50% en 2MN omsetting van 97-99% vir die hidroksilering van 2MN na 2MNK oor hoogs geordende mesoporeuse materiale behaal. Hierdie studie bevestig bevindinge van die literatuur dat die prosesstelsel, reaksiekondisies en katalisatortipe ʼn groot impak het op prosesprodukte, 2MN omsetting, 2MNK selektiwiteit en 2MNK opbrengs. In hierdie navorsingstudie is bevind dat hoë 2MN omsetting en 2MNK opbrengs behaal word by hoë reaksietemperature met kort reaksietye en hoë waterstofperoksiedvolumes. Dit is gevind dat die hoogs geordende mesoporeuse materiaal werklik heterogeen is, aangesien geen loging plaasgevind het nie, en aangesien die katalisator hergebruik kon word sonder verlies aan katalisatoraktiwiteit en –selektiwiteit, vir ten minste twee katalisatorsiklusse. ʼn Gevolgtrekking kan gemaak word dat die hoogs geordende mesoporeuse materiaal ʼn belowende katalisator vir die selektiewe oksidering van lywige substrate met waterige H2O2 is, aangesien dit ʼn omgewingsvriendelike proses lewer met hoë omsetting, hoë kinoonopbrengs en katalisatorgedrag wat waarlik heterogeen is.

Yes / We have used literature values for the solubility of vitamin K3 in organic solvents to obtain Abraham descriptorsfor vitamin K3. Although these descriptors themselves are not exceptional in any way, when combined withequations that we have already set out, they lead to the prediction of important properties of vitamin K3.These include the vapor pressure and heat of sublimation (necessary for the analysis of data on the concentrationof vitamin K3 in ambient air), and the partitions air-water, air-blood, air-lung, air-fat, air-skin, water-lipid, water-membrane, water-skin, as well as permeation from water through skin. Values of the partitions into biologicalphases are all quite large by comparison to those for organic compounds in general.

No description available.

Les peroxyrédoxines sont des enzymes essentielles de la cellule. Outre leur rôle d’antioxydant, elles sont aussi des régulateurs de la signalisation cellulaire et des suppresseurs de tumeurs. La péroxiredoxine 1 (Prx1) est la plus abondante parmi les six isoformes de peroxyrédoxines humaines. Elle est fréquemment surexprimée dans plusieurs types de cellules cancéreuses, et on a pu associer Prx1 aux processus de carcinogenèse et de métastase, ainsi qu’à la résistance à la radiothérapie ou la chimiothérapie. Ainsi, Prx1 pourrait donc être une cible anticancéreuse intéressante. Au cours de ce travail de thèse, nous avons d’abord évalué l'impact d’une diminution de Prx1 (Prx1 knockdown (Prx1–)) sur la sensibilité cellulaire à des dizaines de médicaments anticancéreux dont la vinblastine, le taxol, la doxorubicine, la daunorubicine, l’actinomycine D, et le 5-fluorouracile, et d’agents connus pour provoquer la production d’espèces réactives de l’oxygène (ROS), dont le peroxyde d'hydrogène, le 2-phényléthyle isothiocyanate, le β-lapachone (β-lap) et la ménadione. Nous avons mis en évidence qu’une diminution de Prx1 augmente significativement la sensibilité des cellules à l'effet cytotoxique de la β-lap et de la ménadione, deux naphtoquinones possédant une activité anti-tumorale.Nous avons étudié les mécanismes responsables de l'augmentation de la cytotoxicité de la β-lap dans un contexte Prx1–. Nous montrons que la toxicité accrue de la β-lap dans des cellules Prx1– est due à une accumulation intracellulaire de ROS. Cet effet est dépendant de l’activité NADPH quinone oxydoréductase (NQO1) et s’accompagne d’une phosphorylation de c-Jun N-terminal kinases (JNK), protein 38 (p38), extracellular signal-regulated kinases (Erk) et des mitogen-activated protein kinases (MAPK), mais aussi d’une diminution des niveaux protéiques de la thiorédoxine 1. En se basant sur le fait que Prx1 est une enzyme antioxydante et un partenaire d'au moins ASK1 et JNK, deux éléments clés de la voie MAPK, nous proposons que la sensibilisation à la β-lap, observée après diminution de Prx1, est provoquée par une action synergique entre l'accumulation de ROS et l'induction de la voie MAPK, conduisant ainsi à l'apoptose.Nous avons ensuite étudié les mécanismes responsables de l'augmentation de la cytotoxicité de la ménadione dans le contexte Prx1–. La sensibilité accrue des cellules à l'effet cytotoxique de la ménadione et également associée à l'accumulation rapide et massive des ROS intracellulaire et à une mort cellulaire ressemblant à la nécrose programmée (necroptosis). L’accumulation de ROS induite par la ménadione et très rapidement détectée dans le cytosol, le noyau, et de façon encore plus importante, dans la matrice mitochondriale. Ce phénomène est en corrélation avec l'oxydation importante des thiorédoxine 2 et peroxiredoxine 3, deux protéines antioxydantes localisées dans la mitochondrie. La diminution de l’expression de Prx1 s’accompagne d’une augmentation des quantités tant de l’ARNm que de la protéine NRH: quinone oxydoréductase 2 (NQO2). Cette augmentation de l'activité de NQO2 est en grande partie responsable de l'accumulation intracellulaire de ROS et de la mort cellulaire après le traitement à la ménadione. Nos données révèlent que l’accumulation de ROS dans les cellules Prx1– provient de la résultante entre l’augmentation de leur production par NQO2 au cours du métabolisme de la ménadione et la diminution de leur élimination par Prx1. Enfin et de façon surprenante, selon la nature des naptoquinones (β-lap ou ménadione), les voies métaboliques qui conduisent à l'accumulation des ROS, ou les voies de signalisation et les mécanismes de mort cellulaire impliqués semblent être distincts. / Peroxiredoxins have multiple cellular functions as major antioxidants, signaling regulators, molecular chaperones and tumor suppressors. Peroxiredoxin 1 (Prx1) is the most abundant among the six isoforms of human peroxiredoxins. It is frequently over-expressed in various cancer cells, which is known associated with carcinogenesis, metastasis and resistance to radiotherapy or chemotherapy. Prx1 could thus be an interesting anticancer target. In this study, we first evaluated the impact of Prx1 knockdown (Prx1–) on cellular sensitivity to dozens of anticancer drugs including vinblastine, taxol, doxorubicin, daunorubicin, actinomycin D, and 5-fluorouracil, and of reactive oxygen species (ROS)-generating agents, including hydrogen peroxide, 2-phenylethyl isothiocyanate, β-lapachone (β-lap) and menadione. We observed that Prx1 knockdown significantly enhanced cancer cell sensitivity to β-lap and menadione, two naphthoquinones with anti-cancer activity.We first investigated the underlying mechanisms responsible for the specifically enhanced cytotoxicity to β-lap in a Prx1 knockdown context. Prx1 knockdown markedly potentiated β-lap-induced cytotoxicity through ROS accumulation. This effect was largely NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent and associated with the phosphorylation of c-Jun N-terminal kinases (JNK), protein 38 (p38) and extracellular signal-regulated kinases (Erk) proteins in mitogen-activated protein kinase (MAPK) pathways, and a decrease in thioredoxin 1 protein levels. Based on the fact that Prx1 is a major ROS scavenger and a partner of apoptosis signaling kinase 1 (ASK1) and JNK, two key components of MAPK pathways, we propose that Prx1 knockdown-induced sensitization to β-lap is achieved through the combined action of ROS accumulation and MAPK pathway activation, leading to cell apoptosis.We then investigated the underlying mechanisms responsible for the specifically enhanced cytotoxicity to menadione in Prx1– cells. Enhanced sensitivity to menadione was associated with a rapid and significant intracellular ROS accumulation and necroptotic-like cell death. Menadione-induced ROS accumulation occurred immediately in the cytosol, the nucleus, and even more noticeably in the mitochondrial matrix, correlated with significant oxidation of both mitochondria-localized thioredoxin 2 and peroxiredoxin 3. Prx1 knockdown significantly up-regulated mRNA and protein levels of NRH: quinone oxidoreductase 2 (NQO2). Increased activity of NQO2 was largely responsible for menadione-induced ROS accumulation and consequent cell death. Our data indicate that massive ROS accumulation results from the combined effect of increased ROS generation by higher NQO2 activity during menadione metabolism, and diminished Prx1 scavenging activity. Finally and noteworthy, the metabolic pathways that lead to ROS accumulation, downstream signaling pathways and cell death mechanisms appear to be distinct for β-lap and menadione.