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Omer Kucuk

Publications and source records attributed to Omer Kucuk.

At least 37 records · Page 2Linked to original sources
PubMed2004

Lycopene supplementation prevents the development of spontaneous smooth muscle tumors of the oviduct in Japanese quail.

Leiomyomas (fibroids) are benign tumors of the uterus affecting millions of women. Spontaneous leiomyomas of the oviduct are common tumors of the Japanese quail (Coturnix coturnix japonica), which makes it a good animal model for screening potential agents for testing in the prevention and treatment of human myoma uteri. Because dietary intake of lycopene has been associated with a reduced risk of a variety of human cancers, we investigated the effects of lycopene supplementation on the development of leiomyomas in the oviduct of Japanese quail. We also measured serum levels of oxidative stress markers [malondialdehyde (MDA) and homocysteine], lycopene, vitamins C, E, and A, and tissue biomarkers Bcl-2 and Bax expression. One hundred twenty quails (6 mo old) were assigned to 3 treatment groups consisting of 4 replicates of 10 birds in each group. Birds were fed either a basal diet (group C) or the basal diet supplemented with 100 mg (group L1) or 200 mg (group L2) of lycopene per kilogram of diet. The animals were sacrificed after 285 days and the tumors were identified. Lycopene supplementation decreased the number of leiomyomas compared with control subjects (P=0.056). The tumors in lycopene-fed birds were smaller than those found in control birds (P=0.01). There were no significant differences in the expression of tissue Bcl-2 and Bax among the study groups. Serum vitamins C, E, and A increased (P=0.01), whereas MDA and homocysteine concentrations decreased (P=0.01) with lycopene supplementation. No measurable lycopene could be detected in the serum of control birds, whereas a dose-dependent increase was observed in the serum of lycopene-supplemented birds. The results indicate that dietary supplementation with lycopene reduces the incidence and size of spontaneously occurring leiomyoma of the oviduct in the Japanese quail. Clinical trials should be conducted to investigate the efficacy of lycopene supplementation in the prevention and treatment of uterine leiomyoma in humans.

Animals↗
PubMed2004

Genistein potentiates inhibition of tumor growth by radiation in a prostate cancer orthotopic model.

OBJECTIVE: We have shown previously that pretreatment with genistein potentiated cell killing induced by radiation in human PC-3 prostate carcinoma cell line in vitro. We tested this approach in vivo using an orthotopic prostate carcinoma model of PC-3 cells in nude mice. METHODS: Established prostate tumors were pretreated with p.o. genistein at a dose of 5 mg/d for 2 days followed by tumor irradiation with 5 Gy photons. One day after radiation, genistein was resumed and given every other day for 4 weeks. RESULTS: Genistein combined with radiation caused a significantly greater inhibition of primary tumor growth (87%) compared with genistein (30%) or radiation (73%) alone. The number of metastatic lymph nodes was also significantly decreased following genistein and radiation. Paradoxically, genistein alone increased the size of lymph nodes associated with heavy tumor infiltration. Genistein-treated prostate tumors were large with necrosis, apoptotic cells, and giant cells and have a lower proliferation index than in control tumors. Following radiation, areas of tumor destruction replaced by fibrotic tissue and inflammatory cells as well as giant cells were observed, which are typical of radiation effect. After radiation and genistein treatment, an increase in giant cells, apoptosis, inflammatory cells, and fibrosis was observed with decreased tumor cell proliferation consistent with increased tumor cell destruction. Long-term therapy with genistein after prostate tumor irradiation significantly increased survival. CONCLUSIONS: Genistein combined with prostate tumor irradiation led to a greater control of the growth of the primary tumor and metastasis to lymph nodes than genistein or radiation alone, resulting in greater survival.

Animals↗
PubMed2003

Folic acid mediated attenuation of loss of heterozygosity of DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas.

Loss of heterozygosity (LOH) and/or inactivation of tumor suppressor genes are implicated in the initiation and progression of many malignancies, including colorectal cancer. Although accumulating evidence suggests a chemopreventive role for folate in colorectal cancer, regulatory mechanisms are poorly understood. The primary objective of the current investigation was to determine whether folic acid would prevent LOH of the three tumor suppressor genes, deleted in colorectal cancer (DCC), adenomatous polyposis coli (APC) and p53 in macroscopically normal appearing rectal mucosa of patients with adenomatous polyps. In addition, the effect of folic acid on rectal mucosal proliferation was determined. Twenty patients were randomized in a double-blind study to receive either folic acid 5mg once daily or identical placebo tablets for 1 year. Genomic DNA and total protein were extracted from the rectal mucosa at baseline and after 1 year of treatment and analyzed for LOH and protein levels of APC, DCC and p53 genes. In addition, paraffin-embedded mucosal specimens were analyzed for proliferating cell nuclear antigen (PCNA) immunoreactivity, as a measure of cellular proliferative activity. Folate supplementation prevented LOH of DCC gene in five out of five (100%) patients who demonstrated baseline heterozygosity, whereas two out of four (50%) placebo-treated patients with baseline heterozygosity demonstrated allelic loss. Mucosal protein levels of DCC were also reduced in 7 of 10 (70%) placebo-treated patients compared to only 2 of 10 (20%) of patients treated with folate. Levels increased, however, in eight and three patients in the folic acid and placebo groups, respectively (P<0.02). Folic acid caused no change in allelic status of either APC or p53 gene. Folate supplementation caused a small, but not statistically significant, 16% reduction in mucosal proliferation, whereas placebo treatment resulted in a 88% (P<0.05) increase in this parameter, when compared with the corresponding baseline values. Our results indicate that folic acid prevents an increase in proliferation and arrests LOH of DCC gene and also stabilizes its protein in normal appearing rectal mucosa of patients with colorectal adenomas. Taken together, our data suggest that one of the ways folate may exert its chemopreventive effect is by stabilizing certain tumor suppressor gene(s) and preventing further increases in proliferation.

Adenoma↗
PubMed2003

Expression of EGF-receptor related protein (ERRP) decreases in gastric mucosa during aging and carcinogenesis.

Aging and gastrointestinal malignancies, including that of the stomach are associated with increased activation of EGF-receptor (EGFR). Although the intracellular events that regulate this process are poorly understood, we hypothesize that loss of ERRP (EGFR-related protein; GenBank accession number AF187818), a recently identified negative regulator of EGFR, that possesses a substantial homology to the ligand binding extracellular domain of EGFR, may contribute to this event. In support of our hypothesis, we have observed that in Fischer-344 rats, whereas aging is associated with increased activation of EGFR in the gastric mucosa, expression of ERRP decreases inthis tissue during this period. The latter is accompanied by a concomitant reduction in the amount of TGF-alpha bound to ERRP. In contrast, the amount of TGF-alpha bound to EGFR is found to be higher in the gastric mucosa of aged than in young rats. This is accompanied by a concomitant rise in EGFR levels. In the gastric mucosa, EGFR and ERRP are found to be colocalized. Gastric adenocarcinoma in humans, which has been shown to be associated with increased activation of EGFR, shows a substantial reduction in ERRP expression, when compared with benign tissues. We conclude that increased activation of EGFR in the gastric mucosa during aging and carcinogenesis may partly be due to the loss of ERRP.

Aging↗
PubMed2003

Zinc supplementation alleviates heat stress in laying Japanese quail.

The study was conducted to determine whether zinc supplementation could alleviate the detrimental effects of high ambient temperature (34 degrees C) on egg production, digestibility of nutrients and antioxidant status in laying Japanese quail. Quail (n = 180; 52 d old) were divided into six groups (n = 30/group) and were fed a basal diet or the basal diet supplemented with 30 or 60 mg of zinc (ZnSO(4). H(2)O)/kg diet. Birds were kept at 22 degrees C and 58% relative humidity (RH). At 13 wk of age, the thermoneutral (TN) groups remained at the same temperature, whereas the heat-stress (HS) groups were kept in an environmentally controlled room at 34 degrees C and 42% RH for 3 wk. Heat exposure decreased egg production in birds fed the basal diet (P = 0.001). Linear increases in feed intake (P = 0.01) and egg production (P = 0.004) and improved feed efficiency (P = 0.01) and egg quality variables (P 0.05). Results of the present study suggest that supplementation with 60 mg zinc/kg diet protects quail by reducing the negative effects of heat stress.

Animal Nutritional Physiological Phenomena↗
PubMed2003

Soy isoflavones in the treatment of prostate cancer.

Epidemiological studies suggest an inverse association between soy intake and prostate cancer (Pca) risk. We have previously observed that soy isoflavone genistein induces apoptosis and inhibits growth of both androgen-sensitive and androgen-independent Pca cells in vitro. To determine the clinical effects of soy isoflavones on Pca we conducted a pilot study in patients with Pca who had rising serum prostate-specific antigen (PSA) levels. Patients with Pca were enrolled in the study if they had either newly diagnosed and untreated disease under watchful waiting with rising PSA (group I) or had increasing serum PSA following local therapy (group II) or while receiving hormone therapy (group III). The study intervention consisted of 100 mg of soy isoflavone (Novasoy) taken by mouth twice daily for a minimum of 3 or maximum of 6 mo. Forty-one patients were enrolled (4 in group I, 18 in group II, and 19 in group III) and had a median PSA level of 13.3 ng/ml. Thirty-nine patients could be assessed for response. Soy isoflavone supplementation was given for a median of 5.5 (range 0.8-6) mo per patient. Although there were no sustained decreases in PSA qualifying for a complete or partial response, stabilization of the PSA occurred in 83% of patients in hormone-sensitive (group II) and 35% of hormone-refractory (group III) patients. There was a decrease in the rate of the rise of serum PSA in the whole group (P = 0.01) with rates of rise decreasing from 14 to 6% in group II (P = 0.21) and from 31 to 9% in group III (P = 0.05) following the soy isoflavone intervention. Serum genistein and daidzein levels increased during supplementation from 0.11 to 0.65 microM (P = 0.00002) and from 0.11 to 0.51 microM (P = 0.00001), respectively. No significant changes were observed in serum levels of testosterone, IGF-1, IGFBP-3, or 5-OHmdU. These data suggest that soy isoflavones may benefit some patients with Pca.

Administration, Oral↗
PubMed2003

Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy.

The incidence of non-Hodgkin's lymphoma (NHL) has been increasing and is now the leading cause of death in males aged 15-54. Diffuse large cell lymphoma (DLCL) is the most common subtype of NHL. These cells are notable for the high expression of the transcription factor nuclear factor kappa beta (NF-kappaB), raising the possibility that constitutive activation of the NF-kappaB pathway may contribute to the poor prognosis of DLCL patients. Soy isoflavone genistein promotes apoptosis by decreasing NF-kappaB activity. The combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) remains the standard therapy for DLCL with a cure rate of approximately 40%. The WSU-DLCL(2) cell line and its severe combined immunodeficient (SCID) xenograft have constitutively active NF-kappaB which provides us with an excellent model in which to study NF-kappaB modulation and CHOP sensitization by genistein. The antitumor activity of CHOP with or without a genistein was evaluated in our WSU-DLCL(2) model. In vivo, WSU-DLCL(2)-bearing SCID mice received genistein alone (800 micro g kg(-1) day(-1), p.o. as gavages for 5 days), CHOP alone ("C", 40 mg/kg, i.v.; "H", 3.3 mg/kg, i.v.; "O", 0.5 mg/kg, i.v.; and "P", 0.2 mg/kg, every day for 5 days, p.o.), or genistein for 5 days followed by CHOP. Tumor growth inhibition (T/C), tumor growth delay (T - C), and log(10) kill for genistein, CHOP, and genistein followed by CHOP were 33.6%, 19.2%, and 5.2%; 7, 8, and 17 days; and 1.0, 1.2, and 2.6, respectively. To begin elucidating the mechanism of genistein-induced sensitization of WSU-DLCL(2) cells to CHOP chemotherapy in this xenograft mouse model, we studied the in vitro effect of genistein on WSU-DLCL(2) growth inhibition, cell cycle, Bax:Bcl-2 ratio, NF-kappaB DNA binding, and apoptosis in vitro. At 30 micro M, genistein inhibited the growth significantly, induced G(2)-M arrest, increased Bax:Bcl-2 ratio, decreased NF-kappaB DNA binding, and induced apoptosis. Genistein also inhibited NF-kappaB DNA binding in vivo, whereas CHOP enhanced it. Our results show that genistein has growth modulatory effects on WSU-DLCL(2) cells and enhances the antitumor activity of CHOP. Because soy isoflavone genistein is a widely available nutritional supplement, its use in combination with CHOP chemotherapy should be further explored in a clinical trial in patients with NHL.

Animals↗
PubMed2002

Expression of prostate-specific antigen is transcriptionally regulated by genistein in prostate cancer cells.

Prostate cancer is the second-leading cause of cancer-related deaths in men in the United States. Unfortunately, there is no effective therapy when prostate cancer becomes metastatic and refractory to conventional treatments. For this reason, the identification and exploration of new agents that reduce prostate cancer cell growth are of paramount importance. High consumption of plant-derived phytoestrogens is inversely associated with the incidence and mortality rate of prostate cancer. Previous studies, including our own, have shown that the phytoestrogen genistein inhibits prostate cancer cell growth in vitro and in vivo and decreases secreted and intracellular levels of the androgen-regulated protein prostate-specific antigen (PSA), but the role of genistein as an agonist/antagonist for hormone receptors remains unclear. To elucidate the mechanism by which genistein modulates PSA protein expression in prostate cancer cells, we investigated the effects of genistein on androgen-mediated and estrogen-mediated transcriptional regulation of PSA, androgen receptor (AR) mRNA and protein expression, and the ability of nuclear proteins to bind to androgen-response elements (AREs) in LNCaP cells. We showed that genistein decreased the transcriptional activation of PSA by both androgen-dependent and androgen-independent methods in LNCaP cells. The reduction of androgen-mediated transcriptional activation of PSA was correlated with decreased AR protein and mRNA levels and decreased binding to AREs. In contrast, genistein had differential effects on 17beta-estradiol-mediated PSA expressions. Low concentrations of genistein enhanced 17beta-estradiol-mediated PSA expressions, whereas high concentrations of genistein inhibited estrogen-mediated PSA expression in LNCaP cells. Genistein did not inhibit AR protein expression in the presence of 17beta-estradiol. These results suggest that ligand-dependent differences in the ability to activate PSA expression may contribute to the agonistic/antagonistic responses observed with genistein in prostate cancer cells.

Base Sequence↗
PubMed2002

Chemoprevention of prostate cancer.

Chemoprevention is prevention of cancer by administering natural or synthetic chemicals. Anti-androgens are among the promising chemopreventive agents for prostate cancer because prostate epithelium is androgen dependent. A National Cancer Institute supported large, randomized, clinical prostate cancer chemoprevention trial has been conducted to test the efficacy of finasteride, an inhibitor of 5-a-reductase, which converts testosterone to 5-hydroxy-testosterone. Now the focus is on micronutrients and phytochemicals, which have potential preventive effects against prostate cancer. Lycopene, soy isoflavones, vitamin E and selenium are among the most promising nutritional chemopreventive agents. Another NCI supported large clinical chemoprevention trial was recently started to investigate the efficacy of selenium and vitamin E, alone or in combination in the prevention of prostate cancer. Inclusion of appropriate biomarkers in clinical trials will help elucidate the mechanisms by which genetic and epigenetic pathways of carcinogenesis are modulated by nutrients and phytochemicals.

Animals↗
PubMed2002

Zinc in cancer prevention.

Epidemiologic studies suggest that zinc deficiency may be associated with increased risk of cancer. However, few studies have been conducted with zinc supplementation in animals and humans. Most previous intervention studies have used zinc in combination with several other micronutrients, which make them difficult to interpret. Zinc supplementation is associated with decreased oxidative stress and improved immune function, which may be among the possible mechanisms for its cancer preventive activity. Preclinical and clinical studies need to investigate modulation of genetic and epigenetic pathways of carcinogenesis by zinc.

Animals↗
PubMed2002

Cancer chemoprevention.

Chemoprevention means prevention of cancer by administering chemical compounds. Ideal chemopreventive agents are non-toxic, inexpensive and can be taken orally. A large number of natural and synthetic compounds have cancer preventive properties in cell culture or animal model studies. With the demonstration of tamoxifen's ability to prevent breast cancer in women, the feasibility of chemoprevention in humans has now been firmly established. Current challenge is to build on this success and identify non-toxic chemopreventive agents. A promising area of research is clinical studies with botanicals, cancer preventive compounds in fruits, vegetables and other plants.

Antineoplastic Agents↗
PubMed2002

New opportunities in chemoprevention research.

The importance of prevention in reducing the morbidity and mortality from cancer has been widely recognized. With the demonstration of tamoxifen's ability to prevent breast cancer in women, the feasibility of cancer chemoprevention in humans is now established. Future clinical chemoprevention studies should focus on phytochemicals, cancer preventive compounds in fruits, vegetables and other plants. Many phytochemicals are excellent potential chemopreventive agents, because, in addition to their cancer preventive effects, they are relatively non-toxic and inexpensive, they can be taken orally and some of them have other health benefits as well. New opportunities in clinical chemoprevention research include investigating chemopreventive effects of phytochemicals and conducting studies in patients with cancer. There is also a great need to investigate potential benefits and risks of administering phytochemicals before, during or after conventional therapies, such as surgery, chemotherapy, radiation or hormonal therapy. In addition, administration of chemopreventive agents prior to surgery provides an opportunity to investigate the modulation of genetic and epigenetic pathways by putative cancer preventive compounds and nutrients.

Anticarcinogenic Agents↗
PubMed2002

Effects of lycopene supplementation in patients with localized prostate cancer.

Epidemiological studies have shown an inverse association between dietary intake of lycopene and prostate cancer risk. We conducted a clinical trial to investigate the biological and clinical effects of lycopene supplementation in patients with localized prostate cancer. Twenty-six men with newly diagnosed prostate cancer were randomly assigned to receive a tomato oleoresin extract containing 30 mg of lycopene (n = 15) or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of cell proliferation and apoptosis were assessed by Western blot analysis in benign and cancerous prostate tissues. Oxidative stress was assessed by measuring the peripheral blood lymphocyte DNA oxidation product 5-hydroxymethyl-deoxyuridine (5-OH-mdU). Usual dietary intake of nutrients was assessed by a food frequency questionnaire at baseline. Prostatectomy specimens were evaluated for pathologic stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1, insulin-like growth factor binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. After intervention, subjects in the intervention group had smaller tumors (80% vs 45%, less than 4 ml), less involvement of surgical margins and/or extra-prostatic tissues with cancer (73% vs 18%, organ-confined disease), and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia (33% vs 0%, focal involvement) compared with subjects in the control group. Mean plasma prostate-specific antigen levels were lower in the intervention group compared with the control group. This pilot study suggests that lycopene may have beneficial effects in prostate cancer. Larger clinical trials are warranted to investigate the potential preventive and/or therapeutic role of lycopene in prostate cancer.

Adenocarcinoma↗
PubMed2002

Methods to increase fruit and vegetable intake with and without a decrease in fat intake: compliance and effects on body weight in the nutrition and breast health study.

Dietary patterns that involve a decrease in fat and an increase in fruit and vegetable (FV) intake have been suggested to decrease cancer risks. In this study, intervention methods to selectively modify dietary fat and/or FV intakes were developed. Compliance to the diets and the effects on body weight are shown, because both of these dietary changes can impact on and be confounded by changes in energy intake. A total of 122 women with a family history of breast cancer were randomized onto one of four diets for 12 mo. Counseling methods were devised to increase amount and variety of FV consumed with or without a decrease in fat intake using modified exchange list diets. Women on the low-fat and combination low-fat/high-FV diet arms decreased their fat intakes to approximately 16% of energy. Women on the high-FV and the combination low-fat/high-FV diet arms increased FV intakes to approximately 11 servings/day. Despite counseling efforts to maintain baseline energy intakes, mean body weight increased significantly by 6 pounds in women in the high-FV diet arm and decreased significantly by 5 pounds in women in the low-fat diet arm. Percent body fat also was increased in the high-FV diet arm and decreased in the low-fat diet arm. Body weight and percent body fat in the combination diet arm did not change significantly. Control of energy intake, therefore, appears to have been achieved only when the addition of FV to the diet was balanced by a decrease in fat intake and both dietary components were enumerated daily. Maintenance of energy intake, therefore, did not appear to be attained intrinsically when individuals were counseled to make changes in the composition of their diets.

Adipose Tissue↗
PubMedDate not supplied

Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein.

Prostate cancer frequently metastasizes to the bone, and the treatment outcome for metastatic prostate cancer has been disappointing so far. Dietary genistein, derived primarily from soy product, has been proposed to be partly responsible for the low rate of prostate cancer in Asians. Our previous studies have shown that genistein elicits pleiotropic effects on prostate cancer cells, but there are no studies documenting comprehensive gene expression profiles and antitumor effects of dietary genistein on human prostate cancer grown in human bone environment. In this study, we investigated the effects of genistein on PC3 prostate cancer cells and experimental PC3 bone tumors created by injecting PC3 cells into human bone fragments previously implanted in severe combined immunodeficient (SCID) mice (SCID human model). We found that genistein significantly inhibited PC3 bone tumor growth using both prevention and intervention strategies. By using microarray and real-time polymerase chain reaction technology, we found that genistein regulated the expression of multiple genes involved in the control of cell growth, apoptosis, and metastasis both in vitro and in vivo. For example, the expression of various metalloproteinases (MMPs) in PC3 bone tumors was inhibited by genistein treatment, whereas osteoprotegerin was upregulated. MMP immunostaining and transfection experiments also demonstrated that MMP-9 expression was inhibited in PC3 cells in vitro and PC3 bone tumors in vivo after genistein treatment. These results, particularly the in vivo results, demonstrate that dietary genistein may inhibit prostate cancer bone metastasis by regulating metastasis-related genes. Genistein may thus be a promising agent for the prevention and/or treatment of prostate cancer.

Animals↗
PubMedDate not supplied

EGF-receptor related protein causes cell cycle arrest and induces apoptosis of colon cancer cells in vitro and in vivo.

BACKGROUND: EGF Receptor Related Protein (ERRP), a recently identified negative regulator of EGF-receptor (EGFR), has been shown to inhibit growth of colon cancer xenograft tumors in SCID mice. However, the mechanisms by which ERRP exerts its anti-tumor properties are poorly understood The current investigation was undertaken to delineate the inhibitory mechanisms that are triggered by ERRP. MATERIALS AND METHODS: For in vivo experiments, recombinant ERRP (20 microg/mouse) or an equivalent volume of vehicle was injected (away from the tumor site) every other day for 10 days to SCID mice xenotransplanted with the colon cancer cell line HCT-116 Tumor explants were obtained for further immunohistochemical analysis. For in vitro studies, the HCT-116 cell line was incubated with recombinant ERRP and apoptosis markers and cell cycle changes were evaluated. RESULTS: Recombinant ERRP caused marked inhibition of tumor growth. This was accompanied by increased apoptosis and attenuation of ERK1/2 and Akt activities. Exposure of HCT-116 cells to recombinant ERRP for 24 hours caused apoptosis and cell cycle arrest at G0/1-phase. Induction of apoptosis was evidenced by increased levels of cleaved caspase-3, PARP proteins and acridine orange staining. CONCLUSION: Our findings reveal a pro-apoptotic property of ERRP both in vitro and in vivo. We propose that ERRP functions by inhibiting the activation of the EGF-receptor signaling and its downstream effectors such as ERK and Akt kinases, underscoring the potential of ERRP for the treatment of colorectal cancer where the EGF pathway is known to be activated.

Animals↗