Localization of cyclooxygenases-1 and -2, and prostaglandin F synthase in human kidney and renal cell carcinoma

Sakurai, Madoka; Oishi, Kenji; Watanabe, Kikuko

doi:10.1016/j.bbrc.2005.08.194

Cited by 11 publications

(12 citation statements)

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“…However, as compared with distal tubular epithelial cells, proximal tubular epithelial cells express lower concentrations of COX-1, prostaglandin synthases, and much less COX-2 expression. (20, 31) These are consistent with our own observations. We also did not detect a significant change in COX-1 expression among our cPLA 2 α-silenced cells in contrast to data published by Niknami et al which demonstrated that cPLA 2 α silencing increased COX-1 expression in prostate cancer cells.…”

Section: Discussionsupporting

confidence: 93%

Cytosolic phospholipase A2α increases proliferation and de-differentiation of human renal tubular epithelial cells

Montford

Lehman

Scobey

et al. 2016

Prostaglandins & Other Lipid Mediators

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The group IVA calcium-dependent cytosolic phospholipase A2 (cPLA2α) enzyme controls the release of arachidonic acid from membrane bound phospholipids and is the rate-limiting step in production of eicosanoids. A variety of different kidney injuries activate cPLA2α, therefore we hypothesized that cPLA2α activity would regulate pathologic processes in HK-2 cells, a human renal tubular epithelial cell line, by regulating cell phenotype and proliferation. In two lentiviral cPLA2α-silenced knockdowns, we observed decreased proliferation and increased apoptosis compared to control HK-2 cells. cPLA2α-silenced cells also demonstrated an altered morphology, had increased expression E-cadherin, and decreased expression of Ncadherin. Increased levels of E-cadherin were associated with increased promoter activity and decreased levels of SNAIL1, SNAIL2, and ZEB1, transcriptional repressors of E-cadherin expression. Addition of exogenous arachidonic acid, but not PGE2, reversed the phenotypic changes in cPLA2α-silenced cells. These data suggest that cPLA2α may play a key role in renal repair after injury through a PGE2-independent mechanism.

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Section: Discussionsupporting

confidence: 93%

Cytosolic phospholipase A2α increases proliferation and de-differentiation of human renal tubular epithelial cells

Montford

Lehman

Scobey

et al. 2016

Prostaglandins & Other Lipid Mediators

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“…5B; Supplementary Table S8). Overexpression of AKR1C3 has been documented in carcinomas of the breast (23,37,38), prostate (39)(40)(41), endometrium (42,43), and kidney (44). Surprisingly, the prostate and breast carcinoma cores did not score highly in our screen (see Supplementary Fig.…”

Section: Discussionmentioning

confidence: 86%

The Bioreductive Prodrug PR-104A Is Activated under Aerobic Conditions by Human Aldo-Keto Reductase 1C3

et al. 2010

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PR-104, currently in phase II clinical trials, is a phosphate ester pre-prodrug which is converted in vivo to its cognate alcohol, PR-104A, a prodrug designed to exploit tumor hypoxia. Bioactivation occurs via one-electron reduction to DNA crosslinking metabolites in the absence of oxygen. However, certain tumor cell lines activate PR-104A in the presence of oxygen, suggesting the existence of an aerobic nitroreductase. Microarray analysis identified a cluster of five aldo-keto reductase (AKR) family members whose expressions correlated with aerobic metabolism of PR-104A. Plasmid-based expression of candidate genes identified aldo-keto reductase 1C3 as a novel nitroreductase. AKR1C3 protein was detected by Western blot in 7 of 23 cell lines and correlated with oxic PR-104A metabolism, an activity which could be partially suppressed by Nrf2 RNAi knockdown (or induced by Keap1 RNAi), indicating regulation by the ARE pathway. AKR1C3 was unable to sensitize cells to 10 other bioreductive prodrugs and was associated with single-agent PR-104 activity across a panel of 9 human tumor xenograft models. Overexpression in two AKR1C3-negative tumor xenograft models strongly enhanced PR-104 antitumor activity. A population level survey of AKR1C3 expression in 2,490 individual cases across 19 cancer types using tissue microarrays revealed marked upregulation of AKR1C3 in a subset including hepatocellular, bladder, renal, gastric, and non-small cell lung carcinoma. A survey of normal tissue AKR1C3 expression suggests the potential for tumor-selective PR-104A activation by this mechanism. These findings have significant implications for the clinical development of PR-104. Cancer Res; 70(4); 1573-84.

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“…Tumour hypoxia is common in solid tumours and associated with poor prognosis and resistance to radiotherapy and chemotherapy [6-8]. AKR1C3 has been shown to be up-regulated in some human cancers [9-11]. On this basis, targeting tumour hypoxia and AKR1C3 is a promising approach to cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia is a common feature of many solid tumours and is associated with poor prognosis and resistance to conventional radiotherapy and chemotherapy [5-8]. In addition, AKR1C3 has been shown to be up-regulated in several types of human cancer [3,9-11]. Targeting ACK1C3 and hypoxia in tumours is therefore a novel and promising approach to cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients

McKeage

Wilson

et al. 2011

BMC Cancer

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BackgroundThe phosphate ester PR-104 is rapidly converted in vivo to the alcohol PR-104A, a nitrogen mustard prodrug that is metabolised to hydroxylamine (PR-104H) and amine (PR-104M) DNA crosslinking agents by one-electron reductases in hypoxic cells and by aldo-keto reductase 1C3 independently of oxygen. In a previous phase I study using a q 3 week schedule of PR-104, the maximum tolerated dose (MTD) was 1100 mg/m2 and fatigue, neutropenic fever and infection were dose-limiting. The primary objective of the current study was to determine the dose-limiting toxicity (DLT) and MTD of weekly PR-104.MethodsPatients with advanced solid tumours received PR-104 as a 1-hour intravenous infusion on days 1, 8 and 15 every 28 days with assessment of pharmacokinetics on cycle 1 day 1. Twenty-six patients (pts) were enrolled (16 male/10 female; median age 58 yrs, range 30 to 70 yrs) who had received a median of two prior chemotherapy regimens (range, 0 to 3) for melanoma (8 pts), colorectal or anal cancer (3 pts), NSCLC (3 pts), sarcoma (3 pts), glioblastoma (2 pts), salivary gland tumours (2 pts) or other solid tumours (5 pts). PR-104 was administered at 135 mg/m2 (3 pts), 270 mg/m2 (6 pts), 540 mg/m2 (6 pts), 675 mg/m2 (7 pts) and 900 mg/m2 (4 pts) for a median of two treatment cycles (range, 1 to 7 cycles) and five infusions (range, 1 to 18) per patient.ResultsDose-limiting toxicities (DLTs) during cycle one included grade four thrombocytopenia at 540 mg/m2 (1 of 6 pts) and grade four thrombocytopenia and neutropenia at 900 mg/m2 (2 of 4 pts). At an intermediate dose of 675 mg/m2, there were no DLTs among a total of seven patients given 12 treatment cycles but all experienced moderate to severe (grade 2 to 4) haematological toxicity. Thrombocytopenia was delayed in its onset and nadir, and its recovery was protracted and incomplete in many patients. There were no complete or partial tumour responses. PR-104-induced thrombocytopenia and neutropenia correlated with plasma AUC of PR-104, PR-104A and an oxidative semi-mustard metabolite (PR-104S1), but no more strongly than with PR-104 dose-level. There was no significant correlation between plasma AUC for the reduced metabolites and myelotoxicity.ConclusionsThrombocytopenia, and to a lesser extent neutropenia, was the DLT of weekly PR-104. The MTD was 675 mg/m2/week. PR-104 given weekly may be a suitable protocol for further clinical evaluation as a short course of treatment with fractionated radiotherapy or haematopoietic stem cell support, as its duration of dosing is restricted by delayed-onset and protracted thrombocytopenia.

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Localization of cyclooxygenases-1 and -2, and prostaglandin F synthase in human kidney and renal cell carcinoma

Cited by 11 publications

References 11 publications

Cytosolic phospholipase A2α increases proliferation and de-differentiation of human renal tubular epithelial cells

Cytosolic phospholipase A2α increases proliferation and de-differentiation of human renal tubular epithelial cells

The Bioreductive Prodrug PR-104A Is Activated under Aerobic Conditions by Human Aldo-Keto Reductase 1C3

A phase I trial of PR-104, a pre-prodrug of the bioreductive prodrug PR-104A, given weekly to solid tumour patients

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