Biomedical subjects

Omer Kucuk

Publications and source records attributed to Omer Kucuk.

At least 19 recordsLinked to original sources

PubMed2007

Progression of renal cell carcinoma is inhibited by genistein and radiation in an orthotopic model.

BACKGROUND: We have previously reported the potentiation of radiotherapy by the soy isoflavone genistein for prostate cancer using prostate tumor cells in vitro and orthotopic prostate tumor models in vivo. However, when genistein was used as single therapy in animal models, it promoted metastasis to regional para-aortic lymph nodes. To clarify whether these intriguing adverse effects of genistein are intrinsic to the orthotopic prostate tumor model, or these results could also be recapitulated in another model, we used the orthotopic metastatic KCI-18 renal cell carcinoma (RCC) model established in our laboratory. METHODS: The KCI-18 RCC cell line was generated from a patient with papillary renal cell carcinoma. Following orthotopic renal implantation of KCI-18 RCC cells and serial in vivo kidney passages in nude mice, we have established a reliable and predictable metastatic RCC tumor model. Mice bearing established kidney tumors were treated with genistein combined with kidney tumor irradiation. The effect of the therapy was assessed on the primary tumor and metastases to various organs. RESULTS: In this experimental model, the karyotype and histological characteristics of the human primary tumor are preserved. Tumor cells metastasize from the primary renal tumor to the lungs, liver and mesentery mimicking the progression of RCC in humans. Treatment of established kidney tumors with genistein demonstrated a tendency to stimulate the growth of the primary kidney tumor and increase the incidence of metastasis to the mesentery lining the bowel. In contrast, when given in conjunction with kidney tumor irradiation, genistein significantly inhibited the growth and progression of established kidney tumors. These findings confirm the potentiation of radiotherapy by genistein in the orthotopic RCC model as previously shown in orthotopic models of prostate cancer. CONCLUSION: Our studies in both RCC and prostate tumor models demonstrate that the combination of genistein with primary tumor irradiation is a more effective and safer therapeutic approach as the tumor growth and progression are inhibited both in the primary and metastatic sites.

Animals↗

PubMed2007

Pilot study of intraoperative chemotherapy with cisplatin and 5-fluorouracil in patients with advanced squamous cell carcinoma of the head and neck.

BACKGROUND: Intraoperative manipulation of the tumor during cancer surgery has long been recognized as a source of metastasis and contamination of the surgical wound during tumor removal. We explored the use of intraoperative chemotherapy to minimize the risk of tumor cell implantation and metastasis during head and neck cancer surgery and conducted a dose escalating intraoperative chemotherapy clinical trial designed to assess the feasibility of this approach and associated toxicities in patients with advanced squamous cell carcinoma of the head and neck. METHODS: Fourteen patients were treated with 5-fluorouracil at a dose of 1000 mg/m(2) administered intravenously over an 8-hour period during the surgery with simultaneous cisplatin. The cisplatin dose was escalated and toxicity observed. Cisplatin at 75 mg/m(2) was chosen as the maximum tolerated dose level. RESULTS: One patient experienced a grade 3 nephrotoxicity, 1 patient a grade 1 neuropathy, and 5 patients grade 2 nausea (36%). There were no grade 4 toxicities. CONCLUSION: Intraoperative chemotherapy is feasible, and the combination of cisplatin at 75 mg/m(2) and 5-fluorouracil at 1000 mg/m(2) can be administered during surgery without significant toxicity.

Aged↗

PubMed2006

Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer.

Bone metastasis is very common in advanced prostate cancer. Docetaxel has been shown to improve survival in patients with metastatic prostate cancer. However, treatment with docetaxel is associated with a certain degree of toxicity. Genistein, derived from soybeans, has been found to inhibit cancer cell growth without toxicity. We have recently reported that genistein could potentiate the antitumor activity of chemotherapeutic agents both in vitro and in vivo. However, the molecular mechanism of this novel effect of genistein has not been fully elucidated. In this study, we found that genistein significantly potentiated the antitumor, anti-invasive, and antimetastatic activities of docetaxel both in culture and in severe combined immunodeficient (SCID)-human model of experimental prostate cancer bone metastasis. We further conducted microarray analysis, real-time reverse transcription-PCR, Western blot analysis, small interfering RNA and cDNA transfection, matrix metalloproteinase-9 (MMP-9) activity assay, and invasion assay. We found that the expression of osteoprotegerin (OPG) was induced by genistein and inhibited by docetaxel, whereas genistein significantly down-regulated the expression and secretion of receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) and inhibited osteoclast formation. Moreover, genistein down-regulated the expression and activity of MMP-9, which was induced by docetaxel treatment, and inhibited invasion of PC-3 cells. These results suggest that the observed potentiation of antitumor activity of docetaxel by genistein in the SCID-human model of experimental bone metastasis could be mediated by regulation of OPG/RANK/RANKL/MMP-9 signaling, resulting in the inhibition of osteoclastic bone resorption and prostate cancer bone metastasis. From these results, we conclude that genistein could be a promising nontoxic agent to improve the treatment outcome of metastatic prostate cancer with docetaxel.

Animals↗

PubMed2006

Genistein inhibits radiation-induced activation of NF-kappaB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest.

BACKGROUND: New cancer therapeutic strategies must be investigated that enhance prostate cancer treatment while minimizing associated toxicities. We have previously shown that genistein, the major isoflavone found in soy, enhanced prostate cancer radiotherapy in vitro and in vivo. In this study, we investigated the cellular and molecular interaction between genistein and radiation using PC-3 human prostate cancer cells. METHODS: Tumor cell survival and progression was determined by clonogenic analysis, flow cytometry, EMSA analysis of NF-kappaB, and western blot analysis of cyclin B1, p21WAF1/Cip1, and cleaved PARP protein. RESULTS: Genistein combined with radiation caused greater inhibition in PC-3 colony formation compared to genistein or radiation alone. Treatment sequence of genistein followed by radiation and continuous exposure to genistein showed optimal effect. Cell cycle analysis demonstrated a significant dose- and time-dependent G2/M arrest induced by genistein and radiation that correlated with increased p21WAF1/Cip1 and decreased cyclin B1 expression. NF-kappaB activity was significantly decreased by genistein, yet increased by radiation. Radiation-induced activation of NF-kappaB activity was strongly inhibited by genistein pre-treatment. A significant and striking increase in cleaved PARP protein was measured following combined genistein and radiation treatment, indicating increased apoptosis. CONCLUSION: A mechanism of increased cell death by genistein and radiation is proposed to occur via inhibition of NF-kappaB, leading to altered expression of regulatory cell cycle proteins such as cyclin B and/or p21WAF1/Cip1, thus promoting G2/M arrest and increased radiosensitivity. These findings support the important and novel strategy of combining genistein with radiation for the treatment of prostate cancer.

Anticarcinogenic Agents↗

PubMed2006

Cisplatin-induced antitumor activity is potentiated by the soy isoflavone genistein in BxPC-3 pancreatic tumor xenografts.

BACKGROUND: The activation of nuclear factor kappaB (NF-kappaB) contributes to drug resistance in pancreatic carcinoma. The authors previously showed that the soy isoflavone genistein down-regulates the activation of NF-kappaB in many carcinoma cell lines in vitro. In the current study, they focused their investigation on testing whether the inactivation of NF-kappaB by genistein could enhance cisplatin-induced cell growth inhibition and apoptosis in BxPC-3 cells in vitro and antitumor activity of cisplatin in vivo. METHODS: BxPC-3 cells were preexposed to 25 microM genistein for 24 hours and then exposed to cisplatin (0.5 microM) for an additional 72 hours. A cell growth inhibition assay, an apoptosis assay, and an NF-kappaB electrophoretic mobility shift assay were conducted. For the in vivo study, a xenograft model of BxPC-3 cells in severe combined immunodeficient mice was used. Genistein was given at a dose of 800 microg/kg orally for 5 days, cisplatin was given at a dose of 9 mg/kg as an intraperitoneal bolus, and another group of mice received both cisplatin and genistein (given on Day 1 concurrently followed by genistein for 4 days). RESULTS: The combination of 25 microM genistein with 0.5 microM cisplatin resulted in significantly greater growth inhibition (P < 0.01) and more apoptosis in BxPC-3 cells compared with either agent alone. Preexposure of BxPC-3 cells to genistein abrogated cisplatin-induced activation of NF-kappaB, which appeared to be consistent with the authors' hypothesis. The authors also demonstrated for the first time that the in vivo effect of genistein enhanced the antitumor activity of cisplatin. The tumor weight for the control, genistein, cisplatin, and combined genistein and cisplatin mice was 940 mg, 762 mg, 261 mg, and 108 mg, respectively. Most important, for the first time, the authors observed that the DNA-binding activity of NF-kappaB was inactivated in genistein-treated animal tumors, whereas cisplatin significantly induced NF-kappaB DNA binding activity, and this was completely abrogated in genistein-pretreated tumors that were exposed to cisplatin, consistent with the in vitro data. CONCLUSIONS: Overall, the current results were consistent with the authors' hypothesis and suggested that pretreatment of pancreatic carcinoma cells with genistein down-regulates NF-kappaB activity and contributes toward enhancing the apoptosis-inducing effect of cisplatin, leading to greater antitumor activity in vivo.

Animals↗

PubMed2006

Benefit of postoperative chemoradiotherapy for patients with unknown primary squamous cell carcinoma of the head and neck.

BACKGROUND: Postopertative adjuvant chemoradiotherapy recently became an established modality for patients with selected high-risk locally advanced head and neck cancers. The optimal treatment of unknown primary squamous cell cancer of the head and neck (SCCHN) continues to be controversial, since major randomized studies excluded those patients. METHODS: We conducted a retrospective review of patients treated during 1995 to 2002 for unknown primary SCCHN. All patients were treated with a neck dissection followed by concurrent high-dose cisplatin (100 mg/m(2)) and bilateral neck radiotherapy. RESULTS: Thirty-seven patients were identified with nodal disease distribution of N1 (5%), N2a (22%), N2b (41%), N2c (8%), N3 (22%), and Nx (3%). Modified neck dissection was done on the majority (30/37 = 81%) of patients. With a median follow-up of 42 months among the survivors, very few patients had regional recurrence (5%) or distant failure (11%), and 89% of patients were alive. The actuarial 5-year overall survival rate could not be estimated because there were no deaths beyond 20 months after surgery. Substantial yet acceptable acute and late morbidities were demonstrated in this cohort of patients. CONCLUSIONS: Postoperative chemoradiotherapy is of potential benefit to patients with unknown primary SCCHN by improving survival and reducing failures. This treatment warrants further prospective evaluation.

Adult↗

PubMed2006

Effects of dietary genistein on nutrient use and mineral status in heat-stressed quails.

Genistein is a powerful antioxidant and plays a role in calcium and bone metabolism. We evaluated the efficacy of dietary supplementation with genistein on the nutrient use and mineral concentrations in tibia and serum of quails reared at high environmental temperature (34 degrees C). Two hundred and forty Japanese quails (10 days old) were randomly assigned to 8 treatment groups consisting of 10 replicates of 3 birds. The birds were kept in a temperature-controlled room at 22 degrees C (Thermoneutral, TN groups) or 34 degrees C (for 8 h/d; 09.00 am-05.00 pm; Heat stress, HS groups). Birds were fed either a basal diet (TN and HS) or the basal diet supplemented with 200, 400 or 800 mg of genistein/kg of diet. Heat exposure decreased apparent nutrient digestibility and bone mineralization when the basal diet was fed (P < 0.001). Apparent digestibility of dry matter (DM) (P < 0.05), crude protein (CP) (P < 0.05) and ash (P < 0.01) was significantly improved by genistein supplementation. However, this improvement was not in direct proportion to increased doses of supplement since there was no difference when diets included either 400 or 800 mg genistein/kg of diet (P < 0.05) in birds reared under heat stress. The amounts of Ca, P, Mg, Mn, Zn, Fe and Cu in the excreta decreased (P < 0.01), while Ca, P, Mg, Mn, Zn and Cu concentrations in tibia ash increased in quails reared under heat stress conditions (P < 0.01) with genistein supplementation. Ca and P concentrations in tibia ash were also increased in birds kept under thermoneutral conditions with genistein supplementation. Increased serum alkaline phosphatase activity (P < 0.01) was associated with increasing dietary genistein in all groups. In conclusion, genistein supplementation to the basal diet improved digestibility of CP, DM and ash and levels of Ca and P and bone mineralization in quails reared under heat stress conditions.

Animals↗

PubMed2006

Prostate cancer treatment is enhanced by genistein in vitro and in vivo in a syngeneic orthotopic tumor model.

Pretreatment with genistein, a bioactive component of soy isoflavones, potentiated cell killing induced by radiation in human PC-3 prostate cancer cells in vitro. Using an orthotopic xenograft in nude mice, we demonstrated that genistein combined with prostate tumor irradiation caused greater inhibition of primary tumor growth and increased control of spontaneous metastasis to para-aortic lymph nodes, increasing mouse survival. Paradoxically, treatment with genistein alone increased metastasis to lymph nodes. This observation is of concern in relation to soy-based clinical trials for cancer patients. To address whether this observation is because nude mice have an impaired immune system, these studies were repeated in orthotopic RM-9 prostate tumors in syngeneic C57BL/6 mice. The combination of genistein with radiation in this model also caused a greater inhibition of primary tumor growth and spontaneous metastasis to regional para-aortic lymph nodes, whereas treatment with genistein alone showed a trend to increased lymph node metastasis. Data from the syngeneic and xenograft models are comparable and indicate that the combination of genistein with radiotherapy is more effective and safer for prostate cancer treatment than genistein alone, which promotes metastatic spread to regional lymph nodes.

Animals↗

PubMed2005

Inactivation of nuclear factor kappaB by soy isoflavone genistein contributes to increased apoptosis induced by chemotherapeutic agents in human cancer cells.

Cancer chemotherapeutic strategies commonly require multiple agents. However, use of multiple agents contributes to added toxicity resulting in poor treatment outcome. Thus, combination chemotherapy must be optimized to increase tumor response and at the same time lower its toxicity. Chemotherapeutic agents are known to induce nuclear factor kappaB (NF-kappaB) activity in tumor cells, resulting in lower cell killing and drug resistance. In contrast, genistein has been shown to inhibit the activity of NF-kappaB and the growth of various cancer cells without causing systemic toxicity. We therefore investigated whether the inactivation of NF-kappaB by genistein before treatment of various cancer cells with chemotherapeutic agents could lead to better tumor cell killing as tested by in vitro studies using gene transfections and also by animal studies. PC-3 (prostate), MDA-MB-231 (breast), H460 (lung), and BxPC-3 (pancreas) cancer cells were pretreated with 15 to 30 micromol/L genistein for 24 hours and then exposed to low doses of chemotherapeutic agents for an additional 48 to 72 hours. We found that 15 to 30 micromol/L genistein combined with 100 to 500 nmol/L cisplatin, 0.5 to 2 nmol/L docetaxel, or 50 ng/mL doxorubicin resulted in significantly greater inhibition of cell growth and induction of apoptosis compared with either agent alone. Moreover, we found that the NF-kappaB activity was significantly increased within 2 hours of cisplatin and docetaxel treatment and that the NF-kappaB inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results were also supported, for the first time, by animal experiments, p65 cDNA transfection and p65 small interfering RNA studies, which clearly showed that a specific target (NF-kappaB) was affected in vivo. Collectively, our results clearly suggest that genistein pretreatment inactivates NF-kappaB and may contribute to increased growth inhibition and apoptosis induced by cisplatin, docetaxel, and doxorubicin in prostate, breast, lung, and pancreatic cancer cells. Theses results warrant carefully designed clinical studies investigating the combination of soy isoflavones and commonly used chemotherapeutic agents for the treatment of human cancers.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Epidermal growth factor receptor (EGFR)-related protein inhibits multiple members of the EGFR family in colon and breast cancer cells.

Inactivation of epidermal growth factor receptor (EGFR) family members represents a promising strategy for the development of selective therapies against epithelial cancers. Current anti-EGFR therapies, such as cetuximab (Erbitux), gefitinib (Iressa), or trastuzumab (Herceptin), target EGFR or HER-2 but not both. Because solid tumors express different EGFRs, identification of inhibitor(s), targeting multiple EGFR family members may provide a therapeutic benefit to a broader patient population. We have identified a natural inhibitor of EGFRs called EGFR-related protein (ERRP), a 53 to 55 kDa protein that is present in most, if not all, normal human epithelial cells. The growth of colon (HCT-116, Caco2, and HT-29) and breast (MDA-MB-468 and SKBR-3) cancer cells expressing varying levels of EGFR, HER-2, and/or HER-4 was inhibited by recombinant ERRP in a dose-dependent manner. In contrast, ERRP caused no inhibition of growth of normal mouse fibroblast cell lines (NIH-3T3, NIH-3T3/P67), and the growth of nontransformed rat small intestinal IEC-6 cells expressing relatively low levels of EGFRs was inhibited only at high doses of ERRP. Transforming growth factor-alpha or heparin-binding epidermal growth factor-induced activation of EGFR and HER-2 was inhibited by ERRP in colon and breast cancer cells expressing high levels of EGFR or HER-2. In contrast, cetuximab inhibited the growth- and ligand-induced activation of EGFR in cell lines expressing high levels of EGFR, whereas trastuzumab was effective only in HER-2-overexpressing cells. ERRP and trastuzumab, but not cetuximab, attenuated heregulin-alpha-induced activation of colon and breast cancer cells that expressed high levels of HER-2. Furthermore, ERRP, but not cetuximab or trastuzumab, significantly induced apoptosis of colon and breast cancer cells. None of these agents induced apoptosis of either NIH-3T3 mouse fibroblast or normal rat small intestinal IEC cells. Our results suggest that ERRP is an effective pan-erbB inhibitor and, thus, may be a potential therapeutic agent for a wide variety of epithelial cancers expressing different levels and subclasses of EGFRs.

Animals↗

PubMed2005

Effects of dietary combination of chromium and biotin on growth performance, carcass characteristics, and oxidative stress markers in heat-distressed Japanese quail.

Environmental stress causes adverse effects in performance and antioxidant status of poultry. Dietary chromium supplementation promotes the growth rate and feed efficiency of growing poultry and these beneficial effects of chromium appear to be greater under stress. Biotin, a member of the vitamin B complex, is involved in the metabolism of carbohydrates, fats, and proteins. In a previous experiment, we examined the effects of chromium picolinate (CrPic) as a chromium source in birds subjected to high environmental temperature and the data showed that supplementation with CrPic ameliorated the deletorious effect of stress. The study was conducted to determine the effects of a supplementation of combination of CrPic and biotin (Diachrome ) on performance, carcass characteristics, levels of oxidative stress markers, serum cholesterol, and glucose concentrations in Japanese quail (Coturnix coturnix japonica) exposed to high ambient temperature of 34 degrees C. Two hundred forty Japanese quail (10 d old) were randomly assigned to 8 treatment groups consisting of 10 replicates of 3 birds. The birds were kept in a temperature-controlled room at 22 degrees C (thermo-neutral [TN] groups) or 34 degrees C (for 8 h/d; 09.00 am to 05.00 pm; heat-stress [HS] groups). Birds were fed either a basal (control) diet (TN and HS) or the basal diet supplemented with either 1, 2, or 4 mg of Diachrome/kg of diet. Heat exposure decreased performance when the basal diet was fed (p = 0.001). Diachrome supplementation increased feed intake (p = 0.001), body weight (p = 0.05), feed efficiency (p = 0.01), and carcass traits (p 0.05) the variables measured, with the exception of a reduction in serum cholesterol and glucose. Results of the present study suggest that Diachrome can be considered a protective dietary supplement by reducing the negative effects of high environment temperature on performance and oxidative stress in quail.

Animal Feed↗

PubMed2004

Antioxidant effect of zinc in humans.

Oxidative stress is known to be an important contributing factor in many chronic diseases. We tested the hypothesis that in healthy normal volunteers zinc acts as an effective anti-inflammatory and antioxidant agent. Ten normal volunteers were administered daily oral zinc supplementation (45 mg zinc as gluconate) and 10 volunteers received placebo for 8 weeks. Plasma zinc, MDA, HAE, and 8-OHdG levels; LPS-induced TNF-alpha and IL-1beta mRNA; and ex vivo TNF-alpha-induced NF-kappaB activity in mononuclear cells (MNC) were determined before and after supplementation. In subjects receiving zinc, plasma levels of lipid peroxidation products and DNA adducts were decreased, whereas no change was observed in the placebo group. LPS-stimulated MNC isolated from zinc-supplemented subjects showed reduced mRNA for TNF-alpha and IL-1beta compared to placebo. Ex vivo, zinc protected MNC from TNF-alpha-induced NF-kappaB activation. In parallel studies using HL-60, a promyelocytic cell line, we observed that zinc enhances the upregulation of mRNA and DNA-specific binding for A20, a transactivating factor which inhibits the activation of NF-kappaB. Our results suggest that zinc supplementation may lead to downregulation of the inflammatory cytokines through upregulation of the negative feedback loop A20 to inhibit induced NF-kappaB activation. Zinc administration to human subjects with conditions associated with increased oxidative stress should be explored.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Expression of epidermal growth factor-receptor related protein (ERRP) in human colorectal carcinogenesis.

We hypothesize that ERRP (EGFR-related protein), a recently identified negative regulator of EGFR may modulate EGFR function in colorectal carcinogenesis. The expression of ERRP and EGFR in normal and neoplastic colorectal tissue was examined. ERRP was highly expressed in normal colonic mucosa and benign colorectal adenomas, but lower in colorectal cancer. Mean scores for ERRP expression decreased significantly across well differentiated, moderately well differentiated and poorly differentiated (P = 0.002) tumors, respectively. ERRP expression became more attenuated in polyps with increasing grades of dysplasia. In contrast, expression of EGFR was inversely related to ERRP in representative samples of normal and neoplastic tissues.

Adenoma↗

PubMed2004

Folic acid-mediated inhibition of serum-induced activation of EGFR promoter in colon cancer cells.

Although accumulating evidence suggests a chemopreventive role for folic acid (FA) in colorectal carcinogenesis, the underlying mechanisms are largely unknown. Previously, we reported that supplemental FA inhibits the expression and activation of epidermal growth factor receptor (EGFR) in colon cancer cell lines. To determine the mechanism(s) by which FA affects EGFR function, we have examined whether and to what extent supplemental FA or its metabolites 5-methyltetrahydrofolate (MTF), dihydrofolate (DF), and tetrahydrofolate (TF) will modulate basal and serum-induced activation of the EGFR promoter in the HCT-116 colon cancer cell line. HCT-116 cells were preincubated with or without (control) FA or one of its metabolites (10 microg/ml) for 48 h, transfected with the EGFR promoter luciferase reporter construct, and incubated for 48 h with FA, DF, TF, or 5-MTF in the absence or presence of 10% FBS. Supplemental FA as well as its metabolites markedly inhibited EGFR promoter activity and its methylation status. Exposure of the cells to 10% FBS caused a marked stimulation of EGFR promoter activity and its expression, both of which were greatly abrogated by supplemental FA and 5-MTF. In contrast, serum-induced activation of c-fos promoter activity was unaffected by 5-MTF. The 5-MTF-induced inhibition of serum-mediated stimulation of EGFR promoter activity and EGFR expression was reversed when methylation was inhibited by 5-aza-2'-deoxycytidine. Our data suggest that FA and its metabolite 5-MTF inhibit EGFR promoter activity in colon cancer cells by enhancing methylation. This could partly be responsible for FA-mediated inhibition of growth-related processes in colorectal neoplasia.

Antimetabolites, Antineoplastic↗

PubMed2004

Folic acid reduces nuclear translocation of beta-catenin in rectal mucosal crypts of patients with colorectal adenomas.

We have demonstrated that folic acid inhibits cell proliferation and epidermal growth factor receptor (EGFR) activation in colon cancer cell lines. We examined the effect of one year supplemental folic acid (5 mg/day) on the rectal mucosal expression of beta-catenin and pGSK3beta, known to be affected by EGF-R, in patients with colorectal adenomas. Folic acid treatment significantly reduced nuclear expression of beta-catenin (P < 0.05) and cellular expression of pGSK3beta (P < 0.01) when compared to placebo. Folic acid may exert its chemopreventive effect, at least in part, through inhibition of nuclear translocation of beta-catenin.

Adenoma↗

PubMed2004

Differential expression of hZnT-4 in human prostate tissues.

BACKGROUND: Altered zinc levels in prostate benign prostatic hyperplasia (BPH) and carcinoma is well documented. It is not known whether loss of zinc, necessary to restrain aggressive growth, results from loss of a single specific or multiple zinc transporters. METHODS: Human prostate tissues from patients who underwent radical prostatectomy were screened by RT-PCR analysis for five zinc transporters. Relative cDNA expression was determined in normal, BPH, and tumor specimens and four prostate epithelial cell lines. RESULTS: Surgical specimens were obtained from patients with assigned Gleason scores ranging from 5 to 9. Relative expression of hZIP-1 and hZnT-1 were prominent in most samples with relatively lesser degree of expression of hZIP-2 and no detectable expression of hZnT-3. Expression of hZnT-4 was decreased in BPH and tumor samples compared to normal tissue. CONCLUSIONS: These data suggest that zinc homeostasis in normal prostate tissues results from an interplay of multiple transporters and decreased hZnT-4 expression is associated with prostate tissue abnormalities independent of total cellular zinc content.

Base Sequence↗

PubMed2004

Correlation of histopathological variants, cellular DNA content, and clinical outcome in adenoid cystic carcinoma of the salivary glands.

OBJECTIVE: To study the correlation between flow cytometrically measured DNA ploidy with prognostically important histopathologic groups and clinical outcome in patients with adenoid cystic carcinoma of the salivary glands. STUDY DESIGN: 46 tumor specimens were analyzed flow cytometrically for DNA content and assessed for histological grade. Correlations were made between tumor DNA ploidy and histopathological grade, and disease-free and overall survival of these patients. RESULTS: Of the 46 patients, 31 had a cribiform/tubular histologic pattern, and 15 had a solid pattern. 84% of the tumors with cribriform/tubular pattern were DNA diploid, compared with 33% of tumors that were graded solid. This difference proved to be statistically significant (chi(2)11.75, P = 0.0006). Overall and disease-free survival periods were longer for patients with DNA diploid tumors in both groups, 63% vs. 36% and 62% vs 38%, respectively. CONCLUSIONS: Tumor DNA ploidy correlates with prognostically important tumor histopathology as well as overall and disease-free survival in patients with adenoid cystic carcinoma of the salivary gland. EBM RATING: B-3.

Adult↗

PubMed2004

Apoptosis-inducing effect of chemotherapeutic agents is potentiated by soy isoflavone genistein, a natural inhibitor of NF-kappaB in BxPC-3 pancreatic cancer cell line.

Cancer chemotherapeutic strategies should be devised to provide higher tumor response and lower toxicity for combination chemotherapy. Genistein has been shown to inhibit the growth of various cancer cells in vitro and in vivo without toxicity to normal cells. The antitumor effects of genistein could be in part due to inactivation of NF-kappaB activity. In contrast, chemotherapeutic agents inadvertently induce NF-kappaB activity, which may lead to chemoresistance. In this study, we investigated whether the inactivation of NF-kappaB by genistein would enhance the efficacy of chemotherapeutic agents. BxPC-3 pancreatic cancer cells were pretreated with 30 micromol/L genistein for 24 hours and then exposed to lower concentrations of chemotherapeutic agents for an additional 24 hours. Cell growth inhibition assay, apoptosis assay, and NF-kappaB EMSA were performed. The combination of 30 micromol/L genistein with 1 nmol/L docetaxel or 100 nmol/L cisplatin elicited significantly greater inhibition of cell growth compared with either agent alone. The combination treatment induced more apoptosis in BxPC-3 cells compared with single agents. Moreover, the NF-kappaB activity was significantly increased within 2 hours of docetaxel or cisplatin treatment, and the NF-kappaB-inducing activity of these agents was completely abrogated in cells pretreated with genistein. These results clearly suggest that genistein pretreatment, which inactivates NF-kappaB activity, together with other cellular effects of genistein, may contribute to increased cell growth inhibition and apoptosis inducing effects of nontoxic doses of docetaxel and cisplatin, which could be a novel strategy for the treatment of pancreatic cancer.

Antineoplastic Agents↗