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Biomedical subjects

I Shureiqi

Publications and source records attributed to I Shureiqi.

13 recordsLinked to original sources
PubMed2006

Oxidative metabolism of linoleic acid modulates PPAR-beta/delta suppression of PPAR-gamma activity.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that strongly influence molecular events in normal and cancer cells. PPAR-beta/delta (PPAR-b/d) overexpression suppresses the activity of PPAR-gamma (PPAR-g) and PPAR-alpha. This interaction has been questioned, however, by studies with synthetic ligands of PPARs in PPAR-b/d-null cells, and it is not known whether an interaction between PPAR-b/d and PPAR-g exists, especially in relation to the signaling by natural PPAR ligands. Oxidative metabolites of linoleic and arachidonic acids are natural ligands of PPARs. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), the main product of 15-lipoxygenase-1 (15-LOX-1) metabolism of linoleic acid, downregulates PPAR-b/d. We tested (a) whether PPAR-b/d expression modulates PPAR-g activity in experimental models of the loss and gain of PPAR-b/d function in colon cancer cells and (b) whether 15-LOX-1 formation of 13-S-HODE influences the interaction between PPAR-b/d and PPAR-g. We found that (a) 15-LOX-1 formation of 13-S-HODE promoted PPAR-g activity, (b) PPAR-b/d expression suppressed PPAR-g activity in models of both loss and gain of PPAR-b/d function, (c) 15-LOX-1 activated PPAR-g by downregulating PPAR-b/d, and (d) 15-LOX-1 expression induced apoptosis in colon cancer cells via modulating PPAR-b/d suppression of PPAR-g. These findings elucidate a novel mechanism of the signaling by natural ligands of PPARs, which involves modulating the interaction between PPAR-b/d and PPAR-g.

Adenoviridae↗
PubMed2002

Clinical and economic impact of multiple gated acquisition scan monitoring during anthracycline therapy.

The clinical and economic impacts of monitoring cardiac function in patients given doxorubicin have yet to be determined, especially in relation to patient age, cumulative doxorubicin dose, and the relative efficacies of doxorubicin-based vs alternative regimens. We developed a decision analysis model that includes these factors to estimate the incremental survival benefit and cost-effectiveness of using multiple gated acquisition scans to measure left-ventricular ejection fraction before and during doxorubicin chemotherapy. Probability distributions for the incidences of abnormal left-ventricular ejection fraction findings and congestive heart failure were derived from a retrospective review of 227 consecutive cases at The University of Michigan Medical Center and published findings. Multiple gated acquisition-scan monitoring minimally improved the probability of 5-year survival (<1.5% in the base--case scenario). For patients who received up to 350 mg m(-2) of doxorubicin, multiple gated acquisition-scan screening had an incremental cost of $425 402 per life saved for patients between the ages of 15--39. This incremental cost markedly decreased to $138 191, for patients between the ages of 40--59, and to $86 829 for patients older than 60 years. The small gain in 5-year survival probability secondary to multiple gated acquisition scan monitoring doubled for all age groups when the average cumulative dose for doxorubicin reached 500 mg m(-2). Variations in the cure rate differences between the doxorubicin and alternative regimens had insignificant effects on the improvement in 5-year survival rates from multiple gated acquisition-scan screening. The use of multiple gated acquisition scans for pretreatment screening appears to be more cost-effective for patients who are 40 years or older, when cumulative doxorubicin dose is 350 mg m(-2) or less.

Adolescent↗
PubMed2002

Expression of 12-lipoxygenase as a biomarker for melanoma carcinogenesis.

12-Lipoxygenase (12-LOX), through its metabolite 12( )-hydroxyeicosatetraenoic acid [12( )-HETE], has been demonstrated to play a pivotal role in experimental melanoma invasion and metastasis, and 12-LOX expression may be important in early human melanoma carcinogenesis. We have studied the differences in 12-LOX protein expression during the progression of melanoma from human melanocytic cells to benign and dysplastic naevi to malignant metastatic disease. 12-LOX expression was determined in normal human skin melanocytes and in melanocytes found in compound naevi, dysplastic naevi and melanomas using a platelet-type 12-LOX antibody with a diaminobenzidine immunoperoxidase system detection system and was quantified using the analysis software NIH Image 1.62. Mean cellular pixel densities for 12-LOX staining ( = 50 cells/histological type) were unchanged in compound naevi ( = 0.14) and were increased in dysplastic naevi and melanomas compared with normal skin melanocytes ( = 0.03 and = 0.01, respectively). Similarly, melanomas had higher levels of expression compared with dysplastic naevi ( = 0.03). 12-LOX expression was significantly different between compound naevus and dysplastic naevus melanocytes ( = 0.01). These data suggest that 12-LOX may be an important novel marker for cancer progression within the melanoma system, and therefore could be a useful biomarker and therapeutic target for melanoma chemoprevention.

Arachidonate 12-Lipoxygenase↗
PubMed2001

Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer.

PURPOSE: The primary objective of this phase I trial was to determine the maximum-tolerated dose of radiation that could be delivered to the primary tumor concurrent with full-dose gemcitabine in patients with advanced pancreatic cancer. PATIENTS AND METHODS: Thirty seven patients with unresectable (n = 34) or incompletely resected pancreatic cancer (n = 3) were treated. Gemcitabine was administered as a 30-minute intravenous infusion at a dose of 1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle. Radiation therapy was initiated on day 1 and directed at the primary tumor alone, without prophylactic nodal coverage. The starting radiation dose was 24 Gy in 1.6-Gy fractions. Escalation was achieved by increasing the fraction size in increments of 0.2 Gy, keeping the duration of radiation constant at 3 weeks. A second cycle of gemcitabine alone was intended after a 1-week rest. RESULTS: Two of six assessable patients experienced dose-limiting toxicity at the final planned dose level of the trial (42 Gy in 2.8-Gy fractions), one with grade 4 vomiting and one with gastric/duodenal ulceration. Two additional patients at this dose level experienced late gastrointestinal toxicity that required surgical management. CONCLUSION: The final dose investigated (42 Gy) is not recommended for further study considering the occurrence of both acute and late toxicity. However, a phase II trial of this novel gemcitabine-based chemoradiotherapy approach, at a radiation dose of 36 Gy in 2.4-Gy fractions, is recommended on the basis of tolerance, patterns of failure, and survival data.

Adenocarcinoma↗
PubMed2001

Lipoxygenase modulation to reverse carcinogenesis.

New studies of the relationship between polyunsaturated fatty acid metabolismand carcinogenesis have led to novel molecular targets for cancer chemoprevention research. These targets include procarcinogenic lipoxygenases (LOXs), including 5-, 8-, and 12-LOX, and anticarcinogenic LOXs, including 15-LOX-1 and possibly 15-LOX-2. Recent studies indicate that 15-LOX-1 is down-regulated in colorectal cancer cells and that the ability of nonsteroidal anti-inflammatory drugs, a class of clinically active cancer chemopreventive agents, to induce apoptosis and growth inhibition in these cells was dependent on the induction of 15-LOX-1 and its metabolic product 13-S-hydroxyoctadecadienoic acid. Consistent with the colorectal studies, 15-LOX very recently has shown anticarcinogenic activity in esophageal and prostatic carcinogenesis. Inhibitors of other LOXs (e.g., 5-LOX) have preclinical anticarcinogenic activity and are being developed for clinical chemoprevention study. These and other LOX data led us to propose that the various LOX pathways exist in a dynamic balance that shifts during carcinogenesis toward 5-, 8-, and 12-LOX (and cyclooxygenase-2) and away from 15-LOX. A novel approach for cancer chemoprevention would involve LOX modulators, i.e., agents that can induce the anticarcinogenic and/or inhibit the procarcinogenic LOXs, thereby shifting the balance of LOX activities from procarcinogenic to anticarcinogenic metabolism of polyunsaturated fatty acids.

Animals↗
PubMed2001

Nonsteroidal anti-inflammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression.

In previous studies, we have found that expression of 15-lipoxygenase-1 (15-LOX-1) and its main product, 13-S-hydroxyoctadecadienoic acid, are decreased in human colorectal cancers and that nonsteroidal anti-inflammatory drugs (NSAIDs) can therapeutically induce 15-LOX-1 expression to trigger apoptosis in human colorectal cancer cells. NSAIDs similarly induce apoptosis in esophageal cancer cells, although the mechanisms of these effects remain to be defined. In the present study, we tested whether 15-LOX-1 is down-regulated in human esophageal cancers using paired normal and tumor human surgical samples and whether NSAIDs can up-regulate 15-LOX-1 to restore apoptosis in esophageal cancer cells. We found that: (a) 15-LOX-1 was down-regulated in human esophageal carcinomas; (b) NSAIDs induced 15-LOX-1 expression during apoptosis in esophageal cancer cells; and (c) 15-LOX-1 inhibition suppressed NSAID-induced apoptosis, which was restored by 13-S-hydroxyoctadecadienoic acid but not by its parent compound, linoleic acid. These findings demonstrate that 15-LOX-1 is down-regulated in human esophageal carcinomas and that NSAIDs induce apoptosis in esophageal cancer cells via up-regulation of 15-LOX-1. They also support the concept that the loss of the proapoptotic role of 15-LOX-1 in epithelial cancers is not limited to human colorectal cancers.

Adenocarcinoma↗
PubMed2001

Colonic mucosal prostaglandin E2 and cyclooxygenase expression before and after low aspirin doses in subjects at high risk or at normal risk for colorectal cancer.

UNLABELLED: Development of potential cancer chemopreventive drugs involves the systematic evaluation of these drugs in preliminary Phase I and II studies in human beings to identify the optimal drug dose, drug toxicity, and surrogate end point biomarker modulation. OBJECTIVES: We tested the hypothesis that aspirin, at a single, once-daily 81-mg dose, will reduce colonic mucosal concentration of prostaglandin estradiol (E2) in individuals at high risk for colorectal cancer development similar to our prior observations in a young normal-risk population. METHODS: Aspirin was administered at a dose of 81 mg once daily for 28 days in a cohort of 92 matched high-risk and normal-risk colorectal cancer subjects. Prostaglandin E2 and cyclooxygenase expression were assayed from distal sigmoid biopsies from all of the subjects before and after treatment. RESULTS: The mean prostaglandin E2 for normal-risk subjects before aspirin treatment was 11.3 +/- 1.7 pg/microg (mean +/- SE) tissue protein and after aspirin treatment was 4.9 +/- 0.91 pg/microg tissue protein (P < 0.0001). In high-risk subjects, mean pretreatment prostaglandin E2 was 14.4 +/- 1.7 pg/microg tissue protein and after aspirin treatment was 4.7 +/- 0.70 pg/microg tissue protein (P < 0.0001). Aspirin treatment did not alter cyclooxygenase-1 protein expression. CONCLUSIONS: Aspirin treatment at a dose of 81 mg reduces colorectal mucosal prostaglandin E2 concentration after 28 daily doses. Risk for colorectal carcinoma did not modify colorectal mucosal baseline or post-aspirin prostaglandin E2, or cyclooxygenase expression. Colorectal mucosal prostaglandin concentration may be used as a "drug-effect surrogate biomarker," that is, a surrogate to assess sufficient delivery and tissue effect of a chemopreventive agent.

Adult↗
PubMed2000

15-Lipoxygenase-1 mediates nonsteroidal anti-inflammatory drug-induced apoptosis independently of cyclooxygenase-2 in colon cancer cells.

We previously found (I. Shureiqi et al., Carcinogenesis (Lond.), 20: 1985-1995, 1999; I. Shureiqi et al, J. Natl. Cancer Inst., 92: 1136-1142, 2000) that (a) 15-lipoxygenase-1 (15-LOX-1) protein and its product 13-S-hydroxyoctadecadienoic acid (13-S-HODE) are decreased; and (b) nonsteroidal anti-inflammatory drug (NSAID)-induced 15-LOX-1 expression is critical to NSAID-induced apoptosis in colorectal cancer cells expressing cyclooxygenase-2 (COX-2). We used the NSAIDs sulindac sulfone (COX-2-independent) and NS-398 (a COX-2 inhibitor) to assess NSAID upregulation of 15-LOX-1 in relation to COX-2 inhibition during NSAID-induced apoptosis in the DLD-1 (COX-2-negative) colon cancer cell line. We found that: (a) NSAIDs up-regulated 15-LOX-1, which preceded apoptosis; and (b) 15-LOX-1 inhibition blocked NSAID-induced apoptosis, which was restored by 13-S-HODE but not by its parent, linoleic acid. NSAIDs can induce apoptosis in colon cancer cells via up-regulation of 15-LOX-1 in the absence of COX-2.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) appear to act via induction of apoptosis-programmed cell death-as potential colorectal cancer chemopreventive agents. NSAIDs can alter the production of different metabolites of polyunsaturated fatty acids (linoleic and arachidonic acids) through effects on lipoxygenases (LOXs) and cyclooxygenases. 15-LOX-1 is the main enzyme for metabolizing colonic linoleic acid to 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which induces apoptosis. In human colorectal cancers, the expression of this enzyme is reduced. NSAIDs can increase 15-LOX enzymatic activity in normal leukocytes, but their effects on 15-LOX in neoplastic cells have been unknown. We tested the hypothesis that NSAIDs induce apoptosis in colorectal cancer cells by increasing the protein expression and enzymatic activity of 15-LOX-1. METHODS: We assessed 15-LOX-1 protein expression and enzymatic activity, 13-S-HODE levels, and 15-LOX-1 inhibition in association with cellular growth inhibition and apoptosis induced by NSAIDs (primarily sulindac and NS-398) in two colorectal cancer cell lines (RKO and HT-29). All P values are two-sided. RESULTS: Sulindac and NS-398 progressively increased 15-LOX-1 protein expression in RKO cells (at 24, 48, and 72 hours) in association with subsequent growth inhibition and apoptosis. Increased 13-S-HODE levels and the formation of 15-hydroxyeicosatetraenoic acid on incubation of the cells with the substrate arachidonic acid confirmed the enzymatic activity of 15-LOX-1. Inhibition of 15-LOX-1 in RKO cells by treatment with caffeic acid blocked NS-398-induced 13-S-HODE production, cellular growth inhibition, and apoptosis (P =. 007, P<.0001, and P<.0001, respectively); growth inhibition and apoptosis were restored by adding exogenous 13-S-HODE (P<.0001 for each) but not its parent compound, linoleic acid (P = 1.0 for each). Similar results occurred with other NSAIDs and in HT-29 cells. CONCLUSIONS: These data identify 15-LOX-1 as a novel molecular target of NSAIDs for inducing apoptosis in colorectal carcinogenesis.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2000

Chemoprevention: general perspective.

Chemoprevention is the use of natural or synthetic compounds to block, reverse, or prevent the development of invasive cancers. Cellular carcinogenesis forms the biologic basis for the identification of chemopreventives, assessment of their activity, and ultimately the success or failure of a chemopreventive. Chemopreventive agents undergo multistep evaluations to assess efficacy that are similar in concept but vastly different in practice to standard ablative oncologic therapeutics. In vitro assessments of potential anticarcinogenesis efficacy include measurements of an agent's antioxidant activity, induction of phase II metabolizing enzymes and effects upon cellular proliferation and apoptotic control pathways. In vivo efficacy is assessed primarily in rodent models of carcinogenesis that are specific for a given organ target. The role of genetically modified animal models in the in vivo assessment of chemoprevention agents remains unclear. Clinical assessment of chemopreventive agent efficacy consists of a multistep process of identification of an optimal chemopreventive agent (phase 1), demonstration of efficacy in humans through the modulation of reversal of a tissue, biochemical, and molecular surrogates for neoplastic transformation and invasion (phase 2) and cancer risk reduction in large cohort trials (phase 3). Opportunities and future needs include the development of reliable, predictive in vivo models of carcinogenesis, careful exploration of the preventive pharmacology of therapeutic agents being used for non-cancer prevention indications, and the incorporation of genetic risk cohorts to define cancer chemopreventive efficacy.

Animals↗
PubMed1999

Decreased 13-S-hydroxyoctadecadienoic acid levels and 15-lipoxygenase-1 expression in human colon cancers.

13-S-Hydroxyoctadecadienoic acid (13-S-HODE), the product of 15-lipoxygenase (15-LOX) metabolism of linoleic acid, enhances cellular mitogenic responses to certain growth factors. Other observations have questioned whether 13-S-HODE has tumorigenic effects. Our study evaluated the hypothesis that 15-LOX-1 is overexpressed in colon cancers resulting in an increase in intracellular 13-S-HODE. 15-LOX-1 and 13-S-HODE were quantified using western blots, ELISA and immunohistochemistry in 18 human colon cancers with paired normal colonic mucosa. Additionally, 15-LOX-1 expression was measured by western blots in three transformed colonic cell lines and in a human umbilical vein endothelial cell line. Next, we evaluated 13-S-HODE effects on cellular proliferation, cell cycle distribution and apoptosis in a transformed colonic cell line (RKO). Cell cycle distributions were measured by flow cytometry and apoptosis was assessed by phase contrast microscopy, electron microscopy, flow cytometry and DNA fragmentation assay. 15-LOX-1 immunohistochemistry staining scores were reduced in tumor tissues (P </= 0.0001) and 15-LOX-1 expression was absent in three transformed colonic cell lines. 13-S-HODE levels were also reduced in tumors tissues compared with normal controls by ELISA (median 3.3-fold, P = 0.02) and by immunohistochemistry (P </= 0.0001). In vitro 13-S-HODE inhibited RKO cell proliferation and induced cell cycle arrest and apoptosis. 13-S-HODE produced similar effects in HT-29 cells. Our observations indicate that: (i) human colon cancers are associated with a down-regulation in 15-LOX-1 expression and a reduction in 13-S-HODE intracellular levels; (ii) 13-S-HODE can suppress cell proliferation and induce apoptosis in transformed colonic epithelial cells.

Apoptosis↗
PubMed1999

Chemoprevention of epithelial cancers.

Over the past 2 years, new insights into mutator and stromal epithelial cell interactions have enhanced the understanding of the carcinogenesis process and have identified potential new approaches to chemoprevention in diverse epithelial sites. Data testing the efficacy of chemopreventive agents in genetically mutated animal carcinogenesis models as screening tools for chemopreventive agents remain immature and point to a continued need for chemical carcinogenesis models to screen for the potential efficacy of chemopreventive agents. The Breast Cancer Prevention Trial is a published, risk-reduction trial that demonstrated a tamoxifen-induced reduction of the risk for breast cancer and focused attention on the clinical use of chemopreventive agents in healthy women. This trial highlighted the potential chemopreventive activity of selective estrogen-receptor antagonists as chemopreventives for breast cancer. New data from animal and human models continue to support the development of nonsteroidal anti-inflammatory agents as chemopreventives for colorectal cancer. Micronutrient- and diet-intervention trials for colorectal chemoprevention present a mixed picture. Although calcium and vitamin supplements, including folate, reduce the recurrence of adenomatous polyps in humans, the effect is small. Fiber supplementation does not reduce the incidence of polyps or colorectal cancer. New approaches for the chemoprevention of esophageal adenocarcinomas, hepatomas, and squamous cell skin cancers represent promising new approaches to the chemoprevention of epithelial cancers.

Animals↗