A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model

Basu, Hirak S.; Thompson, Todd A.; Church, Dawn R.; Clower, C.; Mehraein-Ghomi, Farideh; Amlong, Corey A.; Martin, Christopher T.; Woster, Patrick M.; Lindstrom, Mary J.; Wilding, George

doi:10.1158/0008-5472.can-08-2472

Cited by 35 publications

(58 citation statements)

References 32 publications

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“…Superoxide release, as a result of the activity of the latter two enzymes, could be especially important in prostate cancer because of prostaglandin biosynthesis (Schewe, 2002). In addition, deregulated androgen signaling increases ROS in prostate cancer (Ripple et al, 1997;Sun et al, 2001;Tam et al, 2003;Frohlich et al, 2008;Basu et al, 2009), which is consistent with the results of other studies that prostate cancer development is associated with oxidative stress (Paschos et al, 2013).…”

Section: Introductionsupporting

confidence: 87%

Effects of astaxanthin on oxidative stress induced by Cu2+ in prostate cells

Meng

et al. 2017

J. Zhejiang Univ. Sci. B

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Astaxanthin (AST), a carotenoid molecule extensively found in marine organisms and increasingly used as a dietary supplement, has been reported to have beneficial effects against oxidative stress. In the current paper, the effects of AST on viability of prostate cells were investigated by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis and intracellular reactive oxygen species (ROS) levels were determined by flow cytometry; the mitochondrial membrane potential (MMP) was measured by fluorospectrophotometer; and activities of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) were evaluated by a detection kit. The results show that copper ion (Cu 2+ ) induced apoptosis, along with the accumulation of intracellular ROS and MDA, in both prostate cell lines (RWPE-1 and PC-3). AST treatments could decrease the MDA levels, increase MMP, and keep ROS stable in RWPE-1 cell line. An addition of AST decreased the SOD, GSH-Px, and CAT activities in PC-3 cell line treated with Cu 2+ , but had a contrary reaction in RWPE-1 cell lines. In conclusion, AST could contribute to protecting RWPE-1 cells against Cu 2+ -induced injuries but could cause damage to the antioxidant enzyme system in PC-3 cells.

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Section: Introductionsupporting

confidence: 87%

Effects of astaxanthin on oxidative stress induced by Cu2+ in prostate cells

Meng

et al. 2017

J. Zhejiang Univ. Sci. B

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“…MDL 72527, an inhibitor of both SMO and APAO (26,27), has been demonstrated to increase survival in a model of prostate carcinogenesis (45), in addition to decreasing ETBFinduced colon tumorigenesis. The data presented in this study, combined with additional published and preliminary results, argue strongly that it is SMO that plays an important role in the production of inflammation-associated ROS and DNA damage and therefore represents a potential chemopreventive or chemotherapeutic target (21,28).…”

Section: Resultsmentioning

confidence: 99%

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Goodwin¹,

Shields²,

Wu³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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501

353

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It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) upregulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of γ-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N 1 ,N 4 -bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.inflammatory bowel diseases | adenomatous polyposis coli I t is estimated that chronic inflammation associated with microbial infection directly contributes to the etiology of about 20% of epithelial cancers. The chronic inflammatory microenvironment is characterized by immune dysregulation and elevated levels of reactive oxygen species [ROS; including superoxide, hydrogen peroxide (H 2 O 2 ), and singlet oxygen]. These features result in activation of stress response pathways and oncogenes, down-regulation of tumor suppressor genes, cell and tissue damage, and contribute to tumor initiation, promotion, and progression. However, the precise molecular links between inflammation and carcinogenesis remain to be clarified (1, 2).In the colon, alterations in the physiological balance between the diverse and abundant microbiota (w10 12 organisms per gram feces) and the host are a common source of inflammation. Bacteroides spp comprise a significant proportion of colonic commensal bacteria and members of this group include symbionts and the leading human anaerobic pathogen, Bacteroides fragilis. Enterotoxigenic B. fragilis (ETBF) represent a molecular subtype characterized by a single unique virulence determinant, the production and secretion of a 20-kDa metalloprotease enterotoxin (B. fragilis toxin; BFT). ETBF have been epidemiologically associated with acute diarrheal diseases in humans and livestock, inflammatory bowel diseases (IBD), and colorectal cancer (reviewed in ref.3). Exposure of intestinal epithelial cell lines to BFT results in cleavage of the cell adhesion and tumor suppressor protein E-cadherin, ...

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“…Numerous preclinical studies aiming to develop novel therapies for preventing or treating PCs have led to the identification of a variety of potential chemopreventive and chemotherapeutic agents, including natural and dietary compounds and pharmacological agents or gene therapies, to eradicate the total tumor cell mass, including PC stem/progenitor cells and their progenies (76,137,(185)(186)(187)(188)(189)(190)(191)(192)(193)(194)(195)(196)(197)(198).…”

Section: Novel Strategies For Preventing Pc Progression and Overcominmentioning

confidence: 99%

“…Some preclinical investigations aiming to develop novel strategies to prevent PC formation or disease progression have aimed to establish the chemopreventive and anticarcinogenic effects induced by diverse dietary compounds using TRAMP and PTEN knockdown transgenic mouse models of PC (137,(187)(188)(189)(190)(191)(192)(193)(194)198). In fact, the TRAMP and PTEN knockdown transgenic mouse models of PC, which are driven by PC stem/progenitor cells endowed with stem cell-like properties, represent useful animal models to estimate the chemopreventive and chemotherapeutic effects induced by the dietary substances on total PC cell mass and their local microenvironment as well as their potential to reverse the treatment resistance (63,97,98,(181)(182)(183)(184)199,200).…”

Section: Chemopreventive and Chemotherapeutic Effects Of Diverse Dietmentioning

confidence: 99%

“…In fact, the TRAMP and PTEN knockdown transgenic mouse models of PC, which are driven by PC stem/progenitor cells endowed with stem cell-like properties, represent useful animal models to estimate the chemopreventive and chemotherapeutic effects induced by the dietary substances on total PC cell mass and their local microenvironment as well as their potential to reverse the treatment resistance (63,97,98,(181)(182)(183)(184)199,200). Of therapeutic interest, it has been shown that different dietary compounds, including curcumin, lycopene, silibinin, feeding of dibenzoylmethane, green tea polyphenols, genistein, α-difluoromethylornithine, toremifene, R-flurbiprofen, celecoxib and sulindax, or their chemical derivatives, significantly decreased the incidence of PIN lesions and PC formation and/or delayed the disease progression in the TRAMP or PTEN knockdown transgenic mouse models of PC (137,(187)(188)(189)(190)(191)(192)(193)(194)198). The anticarcinogenic effects of these dietary agents, alone or in combination, were mediated at least in part through downregulation of diverse growth factor cascades, including EGFR and sonic hedgehog and their downstream signaling elements such as PI3K/Akt and NF-κB in cancer cells (137,(187)(188)(189)(190)(191)(192)(193)(194)198).…”

Section: Chemopreventive and Chemotherapeutic Effects Of Diverse Dietmentioning

confidence: 99%

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Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

Mimeault

Batra

2011

Mol Med

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Recent gene expression profiling analyses and gain-and loss-of-function studies performed with distinct prostate cancer (PC) cell models indicated that the alterations in specific gene products and molecular pathways often occur in PC stem/progenitor cells and their progenies during prostate carcinogenesis and metastases at distant sites, including bones. Particularly, the sustained activation of epidermal growth factor receptor (EGFR), hedgehog, Wnt/β-catenin, Notch, hyaluronan (HA)/CD44 and stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) during the epithelial-mesenchymal transition (EMT) process may provide critical functions for PC progression to locally invasive, metastatic and androgen-independent disease states and treatment resistance. Moreover, an enhanced glycolytic metabolism in PC stem/progenitor cells and their progenies concomitant with the changes in their local microenvironment, including the induction of tumor hypoxia and release of diverse soluble factors by tumor myofibroblasts, also may promote the tumor growth, angiogenesis and metastases. More particularly, these molecular transforming events may cooperate to upregulate Akt, nuclear factor (NF)-κB, hypoxia-inducible factors (HIFs) and stemness gene products such as Oct3/4, Sox2, Nanog and Bmi-1 in PC cells that contribute to their acquisition of high self-renewal, tumorigenic and invasive capacities and survival advantages during PC progression. Consequently, the molecular targeting of these deregulated gene products in the PC-and metastasis-initiating cells and their progenies represent new promising therapeutic strategies of great clinical interest for eradicating the total PC cell mass and improving current antihormonal treatments and docetaxel-based chemotherapies, thereby preventing disease relapse and the death of PC patients.

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A Small Molecule Polyamine Oxidase Inhibitor Blocks Androgen-Induced Oxidative Stress and Delays Prostate Cancer Progression in the Transgenic Adenocarcinoma of the Mouse Prostate Model

Cited by 35 publications

References 32 publications

Effects of astaxanthin on oxidative stress induced by Cu2+ in prostate cells

Effects of astaxanthin on oxidative stress induced by Cu2+ in prostate cells

Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesis

Frequent Gene Products and Molecular Pathways Altered in Prostate Cancer- and Metastasis-Initiating Cells and Their Progenies and Novel Promising Multitargeted Therapies

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