MK591, a leukotriene biosynthesis inhibitor, induces apoptosis in prostate cancer cells: Synergistic action with LY294002, an inhibitor of phosphatidylinositol 3′-kinase

Sarveswaran, Sivalokanathan; Myers, Charles E.; Ghosh, J. J.

doi:10.1016/j.canlet.2009.10.008

Cited by 22 publications

(35 citation statements)

References 38 publications

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“…The enzyme is overexpressed in prostate adenocarcinoma [136] but the molecular mechanisms for the pro-carcinogenic effects are not completely understood. Inhibition of the enzyme triggers apoptosis in different types of prostate cancer [137–139] and pharmacological interference with other constituents of leukotriene signaling induced similar effects [140]. For instance, the cysteinyl leukotriene receptor 1 (cysLTR1) is overexpressed in prostate cancer and cysLTR1 antagonists inhibit prostate cancer cell growth by up-regulating apoptotic cell death [141].…”

Section: Biological Function Of Mammalian Lox Isoformsmentioning

confidence: 99%

Mammalian lipoxygenases and their biological relevance

Kühn

Banthiya

Leyen

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

467

413

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Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated in cell proliferation and differentiation but also in the pathogenesis of various diseases with major public health relevance. As other fatty acid dioxygenases LOX oxidize polyunsaturated fatty acids to their corresponding hydroperoxy derivatives, which are further transformed to bioactive lipid mediators (eicosanoids and related substances). On the other hand, lipoxygenases are key players in regulation of the cellular redox homeostasis, which is an important element in gene expression regulation. Although the first mammalian lipoxygenases were discovered 40 years ago and although the enzymes have been well characterized with respect to their structural and functional properties the biological roles of the different lipoxygenase isoforms are not completely understood. This review is aimed at summarizing the current knowledge on the physiological roles of different mammalian LOX-isoforms and their patho-physiological function in inflammatory, metabolic, hyperproliferative, neurodegenerative and infectious disorders.

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Section: Biological Function Of Mammalian Lox Isoformsmentioning

confidence: 99%

Mammalian lipoxygenases and their biological relevance

Kühn

Banthiya

Leyen

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

467

413

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“…Similarly, the MEK-ERK pathway is also known to promote growth and survival of a variety of cells including cancer cells [26–28]. Interestingly, we observed no reduction in the phosphorylation of Akt at Ser 473 or the enzymatic activity of Akt when prostate cancer cells are treated with MK591 to undergo apoptosis [29]. MK591 is a widely used specific inhibitor of 5-LOX activity, and it does not inhibit cyclooxygenase, epoxygenase or 12-lipoxygenase activities [30,31].…”

Section: Introductionmentioning

confidence: 98%

Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon

Sarveswaran

Thamilselvan

Brodie

et al. 2011

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Previous studies have shown that human prostate cancer cells constitutively generate 5-lipoxygenase (5-LOX) metabolites from arachidonic acid, and inhibition of 5-LOX blocks production of 5-LOX metabolites and triggers apoptosis in prostate cancer cells. This apoptosis is prevented by exogenous metabolites of 5-LOX, suggesting an essential role of 5-LOX metabolites in the survival of prostate cancer cells. However, downstream signaling mechanisms which mediate the survival-promoting effects of 5-LOX metabolites in prostate cancer cells are still unknown. Recently, we reported that MK591, a specific inhibitor of 5-LOX activity, induces apoptosis in prostate cancer cells without inhibition of Akt, or ERK, two well-characterized regulators of pro-survival mechanisms, suggesting the existence of an Akt and ERK-independent survival mechanism in prostate cancer cells regulated by 5-LOX. Here, we report that 5-LOX inhibition-induced apoptosis in prostate cancer cells occurs via rapid inactivation of protein kinase C-epsilon (PKCε), and that exogenous 5-LOX metabolites prevent both 5-LOX inhibition-induced down-regulation of PKCε and induction of apoptosis. Interestingly, pre-treatment of prostate cancer cells with diazoxide (a chemical activator of PKCε), or KAE1-1 (a cell-permeable, octa-peptide specific activator of PKCε) prevents 5-LOX inhibition-induced apoptosis, which indicates that inhibition of 5-LOX triggers apoptosis in prostate cancer cells via down-regulation of PKCε. Altogether, these findings suggest that metabolism of arachidonic acid by 5-LOX activity promotes survival of prostate cancer cells via signaling through PKCε, a pro-survival serine/threonine kinase.

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“…In addition, novel di-O-prenylated chalcone derivatives have been generated and shown to be potent 5-LOX inhibitors in vivo and to inhibit human breast cancer cell proliferation in vitro [156]. Finally, MK591, a selective 5-LOX inhibitor with promising potential as anti-asthma drug, has been shown to induce human prostate cancer cell apoptosis, thus making this inhibitor a promising anticancer drug [157]. Despite these very promising results, it has been recently shown that some 5-LOX inhibitors might lead to cytotoxic and anti-proliferative effects independently of suppression of 5-LOX activity.…”

Section: Single Versus Dual Inhibition Of Cox and Lox In Tumorigenesismentioning

confidence: 99%

Cyclooxygenases and lipoxygenases in cancer

Schneider

Pozzi

2011

Cancer Metastasis Rev

134

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Cancer initiation and progression are multistep events that require cell proliferation, migration, extravasation to the blood or lymphatic vessels, arrest to the metastatic site, and ultimately secondary growth. Tumor cell functions at both primary or secondary sites are controlled by many different factors, including growth factors and their receptors, chemokines, nuclear receptors, cell–cell interactions, cell–matrix interactions, as well as oxygenated metabolites of arachidonic acid. The observation that cyclooxygenases and lipoxygenases and their arachidonic acid-derived eicosanoid products (prostanoids and HETEs) are expressed and produced by tumor cells, together with the finding that these enzymes can regulate cell growth, survival, migration, and invasion, has prompted investigators to analyze the roles of these enzymes in cancer progression. In this review, we focus on the contribution of cyclooxygenase- and lipoxygenase-derived eicosanoids to tumor cell function in vitro and in vivo and discuss hope and tribulations of targeting these enzymes for cancer prevention and treatment.

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MK591, a leukotriene biosynthesis inhibitor, induces apoptosis in prostate cancer cells: Synergistic action with LY294002, an inhibitor of phosphatidylinositol 3′-kinase

Cited by 22 publications

References 38 publications

Mammalian lipoxygenases and their biological relevance

Mammalian lipoxygenases and their biological relevance

Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down-regulation of protein kinase C-epsilon

Cyclooxygenases and lipoxygenases in cancer

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