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Biomedical subjects

Richard H Bell

Publications and source records attributed to Richard H Bell.

At least 19 recordsLinked to original sources
PubMed2006

Apigenin inhibits pancreatic cancer cell proliferation through G2/M cell cycle arrest.

BACKGROUND: Many chemotherapeutic agents have been used to treat pancreatic cancer without success. Apigenin, a naturally occurring flavonoid, has been shown to inhibit growth in some cancer cell lines but has not been studied in pancreatic cancer. We hypothesized that apigenin would inhibit pancreatic cancer cell growth in vitro. RESULTS: Apigenin caused both time- and concentration-dependent inhibition of DNA synthesis and cell proliferation in four pancreatic cancer cell lines. Apigenin induced G2/M phase cell cycle arrest. Apigenin reduced levels of cyclin A, cyclin B, phosphorylated forms of cdc2 and cdc25, which are all proteins required for G2/M transition. CONCLUSION: Apigenin inhibits growth of pancreatic cancer cells through suppression of cyclin B-associated cdc2 activity and G2/M arrest, and may be a valuable drug for the treatment or prevention of pancreatic cancer.

Apigenin↗
PubMed2006

A novel peptide sansalvamide analogue inhibits pancreatic cancer cell growth through G0/G1 cell-cycle arrest.

Patients with pancreatic cancer have little hope for cure because no effective therapies are available. Sansalvamide A is a cyclic depsipeptide produced by a marine fungus. We investigated the effect of a novel sansalvamide A analogue on growth, cell-cycle phases, and induction of apoptosis in human pancreatic cancer cells in vitro. The sansalvamide analogue caused marked time- and concentration-dependent inhibition of DNA synthesis and cell proliferation of two human pancreatic cancer cell lines (AsPC-1 and S2-013). The analogue induced G0/G1 phase cell-cycle arrest and morphological changes suggesting induction of apoptosis. Apoptosis was confirmed by annexin V binding. This novel sansalvamide analogue inhibits growth of pancreatic cancer cells through G0/G1 arrest and induces apoptosis. Sansalvamide analogues may be valuable for the treatment of pancreatic cancer.

Antineoplastic Agents↗
PubMed2006

Incidence of benign inflammatory disease in patients undergoing Whipple procedure for clinically suspected carcinoma: a single-institution experience.

BACKGROUND: We evaluated the incidence of chronic pancreatitis and chronic bile duct inflammation in patients undergoing pancreaticoduodenectomy (PD) for suspected periampullary cancer. METHODS: Differences between clinical presentation, surgical management, and outcomes were compared between patients with malignancy and benign inflammatory disease. RESULTS: The incidence of chronic inflammatory disease was 12.9% (21/162). Patients with chronic inflammatory disease were associated with a higher incidence of smoking (75.0% versus 64.7%) and chronic alcohol use (66.7% versus 46.2%). Jaundice was significantly more frequent in patients with malignant disease (83.6% versus 42.9%, P < .05). Surgery for chronic inflammatory disease was associated with significantly more intraoperative bleeding (P < .05). CONCLUSIONS: The finding of chronic inflammatory disease after PD for suspected carcinoma is justifiable because (1) none of the available diagnostic modalities are infallible, (2) early treatment of pancreatic cancer is crucial for achieving cure, and (3) PD may relieve clinical symptoms in patients with chronic pancreatitis or pancreatic cancer.

Adolescent↗
PubMed2006

On the mechanisms of 12-O-tetradecanoylphorbol-13-acetate-induced growth arrest in pancreatic cancer cells.

OBJECTIVES: Protein kinase C (PKC) is involved in cell growth, differentiation, and apoptosis. We investigated the effects of the PKC activator, the tetradecanylphorbol acetate (TPA), in human pancreatic cancer cells. METHODS: Cell proliferation was measured by thymidine incorporation. Expression of cell cycle proteins was investigated by Western blot. Real-time reverse transcriptase-polymerase chain reaction was used to measure p21 messenger RNA expression, whereas knockdown of its expression was accomplished with a specific small interferring RNA. Cell cycle phases were determined by flow cytometry. RESULTS: TPA time and concentration dependently inhibited thymidine incorporation in Panc-1 and CD18 cells and induced G2/M cell cycle arrest. The TPA decreased cyclin A and B expression, increased cyclin E, and markedly increased the expression of p21 at both the messenger RNA and protein levels. TPA-induced p21 expression and growth inhibition were blocked by the PKC inhibitor, bisindoylmaleimide. TPA induced extracellular signal-regulated kinase1/2 phosphorylation, whereas the MEK inhibitor, PD98059, blocked the TPA-induced p21 expression. Small interferring RNA targeted to p21 blocked TPA-induced p21 protein expression but not TPA-induced cell growth arrest. CONCLUSIONS: TPA-induced p21 expression is mediated by the MEK/ERK pathway but is not involved in TPA-induced growth inhibition. In contrast, cyclin A and cyclin B are likely involved in TPA-induced G2/M arrest because both proteins are involved in S phase and G2/M transition during cell proliferation.

Cell Division↗
PubMed2005

LTB4 stimulates growth of human pancreatic cancer cells via MAPK and PI-3 kinase pathways.

We have previously shown the importance of LTB4 in human pancreatic cancer. LTB4 receptor antagonists block growth and induce apoptosis in pancreatic cancer cells both in vitro and in vivo. Therefore, we investigated the effect of LTB4 on proliferation of human pancreatic cancer cells and the mechanisms involved. LTB4 stimulated DNA synthesis and proliferation of both PANC-1 and AsPC-1 human pancreatic cancer cells, as measured by thymidine incorporation and cell number. LTB4 stimulated rapid and transient activation of MEK and ERK1/2 kinases. The MEK inhibitors, PD98059 and U0126, blocked LTB4-stimulated ERK1/2 activation and cell proliferation. LTB4 also stimulated phosphorylation of p38 MAPK; however, the p38 MAPK inhibitor, SB203580, failed to block LTB4-stimulated growth. The activity of JNK/SAPK was not affected by LTB4 treatment. Phosphorylation of Akt was also induced by LTB4 and this effect was blocked by the PI-3 kinase inhibitor wortmannin, which also partially blocked LTB4-stimulated cell proliferation. In conclusion, LTB4 stimulates proliferation of human pancreatic cancer cells through MEK/ERK and PI-3 kinase/Akt pathways, while p38 MPAK and JNK/SAPK are not involved.

Androstadienes↗
PubMed2005

Pancreatic stellate cells (PSCs) express cyclooxygenase-2 (COX-2) and pancreatic cancer stimulates COX-2 in PSCs.

BACKGROUND: Cyclooxygenase 2 (COX-2), the inducible form of prostaglandin G/H synthase, is associated with several human cancers including pancreatic adenocarcinoma. Pancreatic stellate cells (PSCs) play a central role in the intense desmoplasia that surrounds pancreatic adenocarcinoma. The present study examined COX-2 expression in PSCs. PSCs isolated from normal rats, were cultured and exposed to conditioned medium (CM) from the human pancreatic cell line, PANC-1. METHODS: COX-2 expression was evaluated by immunostaining and western blotting. Proliferation of PSCs was determined by thymidine incorporation and cell counting. RESULTS: COX-2 was found to be constitutively expressed in PSCs, and COX-2 protein was up-regulated by PANC-1 CM. Moreover, the induction of COX-2 by PANC-1 CM was prevented by U0126, an extracellular signal-regulated kinase (ERK) 1/2 inhibitor suggesting that activation of ERK 1/2 is needed for stimulation of COX-2. Finally, NS398, a selective COX-2 inhibitor, reduced the growth of PSCs by PANC-1 CM, indicating that activation of COX-2 is required for cancer stimulated PSC proliferation. CONCLUSION: The results suggest that COX-2 may play an important role in the regulation of PSC proliferation in response to pancreatic cancer.

Animals↗
PubMed2005

5-Lipoxygenase, a marker for early pancreatic intraepithelial neoplastic lesions.

Pancreatic cancer has an abysmal prognosis because of late diagnosis. Therefore, it is important to identify risk factors if we are to be able to prevent and detect this cancer in an early, noninvasive stage. Pancreatic intraepithelial neoplasias (PanIN) are the precursor lesions which could be an ideal target for chemoprevention. This study shows up-regulation of 5-lipoxygenase (5-LOX) in all grades of human PanINs and early lesions of pancreatic cancer in two different animal models (EL-Kras mice and N-nitrosobis(2-oxopropyl)amine-treated hamsters) by immunohistochemistry. The results were consistent in all tissues examined, including seven chronic pancreatitis patients, four pancreatic cancer patients, one multiorgan donor, nine EL-Kras mice, and three N-nitrosobis(2-oxopropyl)amine-treated hamsters, all with PanINs. Overexpression of 5-LOX in NIH3T3 cells resulted in greater sensitivity of these cells to the growth inhibitory effects of the 5-LOX inhibitor Rev5901. These findings provide evidence that 5-LOX plays a key role in the development of pancreatic cancer. Furthermore, the lipoxygenase pathway may be a target for the prevention of this devastating disease.

Adenocarcinoma↗
PubMed2005

Identification and in silico characterization of a novel gene: TPA induced trans-membrane protein.

12-O-Tetradecanoylphorbol-13-acetate (TPA) is a potent tumor promoter with wide ranging, diverse, and sometimes opposite cellular effects. Using oligonucleotide microarray analysis, we have identified a novel gene that is upregulated following treatment with TPA in the pancreatic cancer cell line CD18. Real-time PCR validated the microarray results in CD18 and HeLa cells, and showed that upregulation of the gene is time- and concentration-dependent. In silico analysis showed the gene product to be a single-pass transmembrane protein of 217 residues that is localized to the endoplasmic reticulum, thus the name TPA induced trans-membrane protein (TTMP). A luciferase reporter assay demonstrated that upregulation of TTMP by TPA is triggered at the promoter level.

Adenocarcinoma↗
PubMed2005

Limited gastric resection.

Despite recent advancements in the staging and treatment of gastric cancer, overall survival remains poor. Extended or radical resections, to include the entire stomach, regional lymph nodes,or contiguous organs, have thus been proposed to alter the course of this fatal disease; however, no prospective randomized trial has validated this approach in a Western center. Furthermore, there are other malignant tumors that occur in the stomach and that may be successfully treated with a limited, nonanatomic, or subtotal gastrectomy, or in the case of gastric lymphoma, without surgery at all. Palliative approaches to patients who have advanced gastric cancer, which should be conservative by nature, are also outlined.

Adenocarcinoma↗
PubMed2005

A novel anti-pancreatic cancer agent, LY293111.

Arachidonic acid is metabolized by two major pathways, cyclooxygenases and lipoxygenases. The metabolites catalyzed by these enzymes are important mediators of acute and chronic inflammation. Both enzymes and their metabolites are well recognized to be involved in cancer development and progress. It is well documented that inhibition of cyclooxygenase 2 (COX-2) activity decreases cancer incidence and inhibits tumor growth. It has also been reported that 5-lipoxygenase is involved in cancer cell survival and proliferation. 5-lipoxygenase metabolites including both 5-HETE and leukotriene (LT) B4 directly mediate cancer cell growth. Although 5-HETE receptors are still elusive, two LTB4 receptor subtypes (BLT1 and BLT2) have been characterized. Both 5-lipoxygenase and LTB4 receptors are upregulated in both pancreatic cancer and early pancreatic cancer lesions; hence, these proteins are potential targets for cancer treatment and prevention. Recent studies have shown that an orally stable leukotriene (LT) B4 receptor antagonist, LY293111, has a potent anti-pancreatic cancer effect. LY293111 inhibits pancreatic cancer growth, induces tumor cell apoptosis both in vitro and in vivo, and enhances the anti-pancreatic cancer effect of gemcitabine. LY293111 exhibits its anti-cancer effects through LTB4 receptors and peroxisome-proliferator activated receptor-gamma. A phase I clinical trial indicated that LY293111 is well tolerated by patients with no significant side-effects. LY293111 may be a valuable drug for treatment of pancreatic cancer, especially in combination with gemcitabine. A double-blinded, placebo-controlled phase II clinical trial with LY293111 is currently underway. This review summarizes the current research status of LY293111 as an anti-cancer agent with a focus on pancreatic cancer.

Animals↗
PubMed2005

LY293111 improves efficacy of gemcitabine therapy on pancreatic cancer in a fluorescent orthotopic model in athymic mice.

Pancreatic cancer has an abysmal prognosis because of late diagnosis and lack of effective therapeutics. New drugs are desperately needed. The present study determined the effect of the LTB4 receptor antagonist, LY293111, on tumor growth and metastases in a fluorescent orthotopic model of pancreatic cancer. Pancreatic cancer cells (S2-013) with stable expression of enhanced green fluorescent protein were implanted into the duodenal pancreatic lobe of athymic mice. Animals were allocated to four groups (eight mice per group): control (no treatment); LY293111; gemcitabine; and LY293111 + gemcitabine. Monitoring of the surgical procedure and follow-up examinations at 2, 3, and 4 weeks after implantation to monitor tumor growth and metastases were performed using a fluorescence microscope and the reversible skin-flap technique. A staging and scoring system was developed to evaluate tumor progression, based on the TNM classification. Control animals developed end-stage disease with invasive cancer, metastases, and cachexia. Tumor growth and incidence of metastases were significantly reduced in all treated mice. However, combined treatment with LY293111 and gemcitabine was most effective. LY293111 is a novel therapeutic agent for pancreatic cancer, which improves the efficacy of gemcitabine. It is well tolerated and can be administered orally and, therefore, provides a new hope for patients suffering from pancreatic adenocarcinoma.

Administration, Oral↗
PubMed2004

Pancreatic cancer stimulates pancreatic stellate cell proliferation and TIMP-1 production through the MAP kinase pathway.

Pancreatic adenocarcinoma is characterized by an intense desmoplastic reaction that surrounds the tumor. Pancreatic stellate cells (PSCs) are thought to be responsible for production of this extracellular matrix. When activated, PSCs have a myofibroblast phenotype and produce not only components of the extracellular matrix including collagen, fibronectin, and laminin, but also matrix metalloproteinases and tissue inhibitors of metalloproteinases (TIMPs). Since PSCs are found in the stroma surrounding human pancreatic adenocarcinoma, we postulate that pancreatic cancer could impact PSC proliferation and TIMP-1 production. Rat PSCs were isolated and cultured. Isolated PSCs were exposed to PANC-1 conditioned medium (CM) and proliferation, activation of the mitogen-activated protein (MAP) kinase pathway, and TIMP-1 gene induction were determined. Exposure to PANC-1 CM increased PSC DNA synthesis, cell number, and TIMP-1 mRNA (real-time PCR) as well as activating the extracellular-regulated kinase (ERK) 1/2. Inhibition of ERK 1/2 phosphorylation (U0126) prevented the increases in growth and TIMP-1 expression. PANC-1 CM stimulates PSC proliferation and TIMP-1 through the MAP kinase (ERK 1/2) pathway.

Adenocarcinoma↗