Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells

We studied the effect of doxorubicin on the production of hydrogen peroxide by PC3 human prostate cancer cells, using a sensitive assay based on aminotriazole-mediated inhibition of catalase. PC3 cells exposed to increasing concentrations of doxorubicin had an increase in intracellular hydrogen peroxide that was concentration-dependent up to 1 μM doxorubicin. The apparent hydrogen peroxide concentration in the PC3 cells was 13 ± 4 pM under basal steady-state conditions and increased to 51 ± 13 pM after exposure to 1 μM doxorubicin for 30 min. The level of hydrogen peroxide in the medium as measured by Amplex Red did not increase as a result of doxorubicin treatment. PC3 cells overexpressing catalase were no more resistant to doxorubicin cytotoxicity as compared to non-transduced wild-type cells; therefore, the exact role of hydrogen peroxide in anthracycline cytotoxicity remains unproven. This study demonstrates that a specific oxidative event associated with the exposure of PC3 human prostate cancer cells to anthracyclines results in an increase in intracellular hydrogen peroxide. KeywordsHydrogen peroxide; Doxorubicin; PC3 cells; Catalase; Transduction; Amplex Red; Oxidative stress; Aminotriazole; Fluorescent probes; Reactive oxygen species There are reports that suggest that anthracycline anti-cancer drugs may increase the intracellular production of hydrogen peroxide. The metabolic reductive activation of doxorubicin to a semiquinone (Eq. 1) stimulates production of superoxide by the oneelectron reduction of oxygen (Eq. 2) [1]. The dismutation of the resulting superoxide,

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“…This is similar to the value reported earlier for PC3 cells of 7 k mU/mg [37]. Others have reported somewhat higher values [38].…”

Section: Discussionsupporting

confidence: 81%

Doxorubicin increases intracellular hydrogen peroxide in PC3 prostate cancer cells

Wagner¹,

Evig²,

Reszka³

et al. 2005

Archives of Biochemistry and Biophysics

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“…Similarly, cells in which mitochondrial transcription factor A (TFAm) is knocked down, rendering them incapable of making mitochondria, cannot produce reactive oxygen species nor can they stabilize HIF1α under hypoxic conditions 30 . Finally, overexpression of manganese superoxide dismutase (MnSOD, also known as SOD2), the mitochondrial sOD, has been shown to inhibit HIF1α levels, downregulate VEGF and inhibit tumour growth 44,45 .…”

Section: Free Radical Regulation Of Hif1 Under Hypoxic Conditionsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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“…SOD2 plays a pivotal role in protecting cells from reactive oxygen species -induced oxidative damage and is a known tumor suppressor in prostate cancer cells (1,(3)(4)(5). The Ala variant of SOD2 allows more efficient SOD2 import into the mitochondrial matrix and generates more active SOD2 compared with the Val variant (14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

“…Among the three isoforms of SOD (SOD1, CuZn-SOD; SOD2, MnSOD; and SOD3, EC-SOD), SOD2 plays an important role as a primary mitochondria antioxidant enzyme and suppresses the growth of prostate cancer cells (1,(3)(4)(5). In this gene, several polymorphisms have been found, including Ex2+24T>C (V16A), which has been widely evaluated for association with various cancers, including prostate cancer (6)(7)(8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Functional Variant of Manganese Superoxide Dismutase (SOD2 V16A) Polymorphism Is Associated with Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Study

Kang

Lee

Park

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

125

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Superoxide dismutase (SOD) plays a key role in the detoxification of superoxide free radicals. We evaluated the association of prostate cancer with genetic polymorphisms in SOD1 (CuZn-SOD; IVS3-251A>G), SOD2 [MnSOD; Ex2+24T>C (V16A)], and SOD3 (EC-SOD; IVS1+186C>T, Ex3-631C>G, Ex3-516C>T, and Ex3-489C>T), the three main isoforms of SOD. Prostate cancer cases (n = 1,320) from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were frequency matched to nondiseased controls (n = 1,842) by age, race, time since initial screening, and year of blood draw. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI); stratified analysis by the level of antioxidative vitamins was also conducted. The higher activity Ala variant at SOD2 Ex2+24T>C (V16A), which has been hypothesized to suppress prostate carcinogenesis, was associated with elevation of prostate cancer risk in Caucasians (Val/Ala versus Val/Val: OR, 1.17; 95% CI, 0.97-1.42; Ala/Ala versus Val/Val: OR, 1.28; 95% CI, 1.03-1.60; P trend = 0.03). Stratification by quartiles of dietary and supplemental vitamin E intake (IU/d) showed risks of prostate cancer tended to be increased among SOD2 Ala allele carriers, except at the highest quartile of vitamin E intake (>222; P interaction = 0.06, Q1-Q3 versus Q4). The association between Ala allele and prostate cancer risk among those with lower intake of vitamin E (V222) was stronger for smokers (OR, 1.44; 95% CI, 1.10-1.90). No significant association with prostate cancer was observed for polymorphic variants in SOD3 or SOD1. These results suggest that the Ala variant of SOD2 is associated with moderately increased risk of prostate cancer, particularly among men with lower intakes of dietary and supplemental vitamin E. (Cancer Epidemiol Biomarkers Prev 2007;16(8):1581-6)

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Manganese superoxide dismutase overexpression inhibits the growth of androgen-independent prostate cancer cells

Cited by 144 publications

References 46 publications

Doxorubicin increases intracellular hydrogen peroxide in PC3 prostate cancer cells

Doxorubicin increases intracellular hydrogen peroxide in PC3 prostate cancer cells

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Functional Variant of Manganese Superoxide Dismutase (SOD2 V16A) Polymorphism Is Associated with Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Study

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