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Inositol hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate that is found in food sources high in fiber content. IP6 has been reported to have significant inhibitory effects against a variety of primary tumors. We hypothesized that IP6 would inhibit the cell growth rate of Barrett's adenocarcinoma in vitro. Two Barrett's-associated adenocarcinoma cell lines, SEG-1 and BIC-1, were treated with IP6 at 0.5, 1.0 and 5.0 mM concentrations. Cell viability was measured by MTT assay. Apoptosis and necrosis were evaluated by the Annexin V FITC assay. Reductions (P<0.001) in cellular proliferation were observed in both cell lines. IP6 decreased late apoptosis and necrosis in BIC cells, whereas in SEG-1 cells, early apoptosis, late apoptosis and necrosis were all increased by IP6. IP6 decreases cellular growth by pro-apoptotic mechanisms. Our findings suggest that IP6 has the potential to become an effective adjunct for Barrett's adenocarcinoma. Further studies are needed to evaluate safety and clinical utility of this agent in patients with Barrett's adenocarcinoma.

Introduction: Pancreatic cancer is an extremely virulent form of cancer with few effective treatments. Catechin and inositol hexaphosphate (IP6), two naturally occurring molecules found in green tea and high-fiber foods, respectively, are compounds that have been shown to demonstrate anti-proliferative effects when administered as single therapeutic agents against a number of cancers. We hypothesized that, alone and in combination, IP6 and catechin would be effective against pancreatic cancer., Materials and Methods: Pancreatic (PANC-1 and MIAPACA) cancer cell lines were cultured and treated with IP6 (0.8 mM/well), catechin (100 microM/well), and the combination of the two. Cell viability was measured by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) at 24, 48, and 72 h. Vascular endothelial growth factor (VEGF) was measured in the cell supernatants by ELISA. Apoptosis was evaluated by Annexin V-fluorescein isothiocyanate (FITC)., Results: The combination of catechin and IP6 significantly inhibited proliferation in the PANC-1 cell line at 24, 48, and 72 h compared to single agents (P < 0.001). Growth of the MIAPACA cell line was inhibited (P < 0.01) by each agent alone, but additive inhibitory effects were not seen. An increase in early apoptosis was attributed to catechin therapy in both cell lines (P < 0.01). The combination of these agents also increased early apoptotic activity when compared to the control (P < 0.001). IP6 reduced VEGF in both cell lines (P < 0.01). In combination, catechin and IP6 amplified VEGF reduction compared to each agent in MIAPACA and control (P < 0.002)., Conclusions: These results, combined with the prevalence of these compounds in safe, naturally occurring foods, make catechin and IP6 attractive therapies for treatment, and possibly in preventative trials, of pancreatic cancer.

Background: Inositol Hexaphosphate (IP6) is a naturally occurring polyphosphorylated carbohydrate found in food sources high in fiber content. We have previously reported IP6 to have significant inhibitory effects against pancreatic cancer in vitro. We hypothesized that the IP6 would significantly inhibit cell growth of cutaneous melanoma in vitro., Materials and Methods: The melanoma line HTB68 was cultured using standard techniques and treated with IP6 at doses ranging from 0.2 to 1.0 mM/well. Cell viability was measured by MTT at 72 h. VEGF production was measured in the cell supernatants by ELISA. Apoptosis was evaluated by Annexin V-FITC and results calculated using FACS analysis. Statistical analysis was performed by ANOVA., Results: Significant reductions (P < 0.001) in cellular proliferation were observed with IP6. Overall, IP6 exhibited a mean inhibition of cell growth of 52.1 +/- 11.5% (range, 1.6-83.0%) at 72 h of incubation. VEGF production was significantly reduced (P < 0.001) by the addition of IP6 (7.5 pg/ml) compared to control (40.9 pg/ml). IP6 significantly increased (P = 0.029) late apoptosis from 5.3 to 7.0% gated events. No changes in necrosis or early apoptosis were observed., Conclusions: Adjuvant treatment of melanoma continues to challenge clinicians and patients. Our findings that IP6 significantly decreased cellular growth, VEGF production and increased late apoptosis in melanoma suggest its potential therapeutic value. Further in vivo studies are planned to evaluate safety and clinical utility of this agent.

Background: We hypothesized that keyhole limpet hemocyanin (KLH) would reduce cellular proliferation and effect apoptosis of melanoma cell lines in vitro., Methods: Two human melanoma cell lines (HTB68 and HTB72) were subjected to a dose-response treatment regimen of KLH (0.4 microg to 100 microg/well). Cell viability was tested by MTT assay (SIGMA, St Louis, MO) at 72 hours. Apoptosis and necrosis were measured by the Annexin V FITC assay (Biovision Inc, Mountain View, CA)., Results: Melanoma cell proliferation was significantly reduced in the HTB68 cell line treated with 6.3 microg or higher doses of KLH. A significant reduction in cell growth was also observed in the HTB72 cells at 50 and 100 microg of KLH. KLH increased early apoptotic activity, whereas both late apoptosis and necrosis were decreased by the addition of KLH., Conclusions: KLH significantly reduces cellular proliferation in vitro in melanoma, via early apoptotic pathways. The results warrant in vivo studies into the effects of KLH in melanoma.

Background: Pentosan polysulfate (Elmiron); (Alza Pharmaceuticals, Mountain View, CA) is the only Food and Drug Administration-approved oral therapy for interstitial cystitis (IC). Women with IC and breast cancer are often in the same age range; therefore, we hypothesize that pentosan polysulfate may also have a therapeutic effect on breast cancer cells in vitro., Methods: Breast cancer lines MCF-7, ZR75-1, and HTB26 were treated with pentosan polysulfate at various concentrations. Cell viability was measured at 24 hours by MTT. Annexin V assay was used to determine the effect of pentosan polysulfate on apoptotic and necrotic activity., Results: Pentosan polysulfate significantly inhibited the growth of the ZR75-1 cells; however, significant cellular proliferation was observed in the MCF-7 cells. A significant change in late apoptotic activity was observed with pentosan polysulfate treatment in vitro., Conclusions: Caution should be used in prescribing pentosan polysulfate for the treatment of IC in patients who are both in high-risk groups for breast cancer and premenopausal females.

Background: Peptide YY (PYY) is an endogenous gut hormone that inhibits the growth of certain cancers. Adenocarcinoma of the esophagus usually arises from Barrett's esophagus. We hypothesized that treatment of Barrett's adenocarcinoma with PYY would result in decreased proliferation., Methods: Barrett's cancer cell lines (BIC and SEG-1) were treated with PYY (3-36) at 500 pmol/mL. Viability was measured by MTT at 24 and 72 hours. Apoptosis and necrosis was evaluated by flow cytometry., Results: PYY reduced proliferation in SEG-1 cells at 24 hours (21.2% +/- 3.4%, P <0.001) and 72 hours (14.2% +/- 6.2%, P <0.001). In the BIC cells, growth was inhibited by 7.9% +/- 7.0%, P = 0.021 after 72 hours. PYY increased late apoptotic activity in SEG-1 cells by 31%, P = 0.014., Conclusions: This is the first report of antiproliferative effects of PYY against Barrett's carcinoma in vitro. Reductions in cell growth appear to be mediated by proapoptotic mechanisms. Further investigation of PYY in the treatment of Barrett's adenocarcinoma is warranted.

Background: Esophageal adenocarcinoma often arises from Barrett’s esophagus. Mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) play critical roles in cell survival. We hypothesized that inhibition of these pathways in Barrett’s adenocarcinoma would decrease cell proliferation and alter apoptosis in vitro. Materials and methods: Two Barrett’s-associated adenocarcinoma cell lines, SEG-1 (wild-type p53) and BIC-1 (mutant p53), were treated with MAPK (U0126) and PI3K (LY294002) inhibitors at 20 μm concentrations. After 24 and 72 h, cell viability was measured by MTT assay. Apoptosis and necrosis were evaluated by the Annexin V-FITC assay. Statistical analysis was performed by ANOVA. Results: LY294002 and U0126 treatment produced significant reductions (range 15.7 to 62.0%, P &#60; 0.05) in cellular proliferation at both 24 and 72 h in the SEG-1 cells. BIC-1 cell viability was reduced (39.3 to 56.4%, P &#60; 0.05) at 72 h. Both early and late apoptotic activity were significantly increased (P &#60; 0.05) in the SEG-1 cells using both inhibitors. Necrosis was significantly reduced (P &#60; 0.05) using both inhibitors. No changes in either early or late apoptosis or necrosis were observed in the BIC-1 cells. Conclusions: Herein, we report significant antiproliferative effects against Barrett’s adenocarcinoma by MAPK and PI3K inhibition in vitro. Pro-apoptotic mechanisms prevail in the wild-type p53 cells. Further investigation is warranted to advance the clinical treatment of this devastating disease. [Copyright &y& Elsevier]

Abstract: Background: We hypothesized that combined treatment with cyclooxygenase (Cox)-1 (catechin) and Cox-2 (NS398)–specific inhibitors would reduce cellular proliferation synergistically in genitourinary cancer. Methods: Bladder (T24 and TCCSUP) and prostate (DU145, LnCaP, and PC3) cancer cell lines were treated with catechin and NS398 at a dose of 100 μmol/L as single and combined treatments. Viability was measured by MTT assay at 24 and 72 hours. Results: Significant synergism of Cox-1 and Cox-2 inhibitors was observed in both bladder cancer lines at both 24 and 72 hours. Synergism of Cox-1 and -2 inhibitors also was noted in the DU145 cells at 72 hours, LnCap cells at 24 hours, and PC3 at both 24 and 72 hours. Conclusions: Significant synergistic effects exhibited by the combination of Cox-1 and Cox-2 inhibitors suggest that these could become a highly effective treatment modality for carcinoma of both the bladder and prostate. [Copyright &y& Elsevier]