Glycogen synthase kinase-3 inhibitor AR-A014418 suppresses pancreatic cancer cell growth via inhibition of GSK-3-mediated Notch1 expression

AbstractBackgroundGlycogen synthase kinase-3 (GSK-3) can act as either a tumour promoter or suppressor by its inactivation depending on the cell type. There are conflicting reports on the roles of GSK-3 isoforms and their interaction with Notch1 in pancreatic cancer. It was hypothesized that GSK-3α stabilized Notch1 in pancreatic cancer cells thereby promoting cellular proliferation.MethodsThe pancreatic cancer cell lines MiaPaCa2, PANC-1 and BxPC-3, were treated with 0–20 μM of AR-A014418 (AR), a known GSK-3 inhibitor. Cell viability was determined by the MTT assay and Live-Cell Imaging. The levels of Notch pathway members (Notch1, HES-1, survivin and cyclinD1), phosphorylated GSK-3 isoforms, and apoptotic markers were determined by Western blot. Immunoprecipitation was performed to identify the binding of GSK-3 specific isoform to Notch1.ResultsAR-A014418 treatment had a significant dose-dependent growth reduction (P< 0.001) in pancreatic cancer cells compared with the control and the cytotoxic effect is as a result of apoptosis. Importantly, a reduction in GSK-3 phosphorylation lead to a reduction in Notch pathway members. Overexpression of active Notch1 in AR-A014418-treated cells resulted in the negation of growth suppression. Immunoprecipitation analysis revealed that GSK-3α binds to Notch1.ConclusionsThis study demonstrates for the first time that the growth suppressive effect of AR-A014418 on pancreatic cancer cells is mainly mediated by a reduction in phosphorylation of GSK-3α with concomitant Notch1 reduction. GSK-3α appears to stabilize Notch1 by binding and may represent a target for therapeutic development. Furthermore, downregulation of GSK-3 and Notch1 may be a viable strategy for possible chemosensitization of pancreatic cancer cells to standard therapeutics

The Changing Presentation of Choledochal Cyst Disease: An Incidental Diagnosis

Background. Choledochal cysts are uncommon biliary lesions. Due to the evolution of imaging and laparoscopic surgery, we sought to describe our last 3 years experience with the presentation and management of choledochal cysts in adults. Methods. A retrospective review of a prospectively established database of adults who were managed for primary choledochal cyst disease between 2005 and 2008 was performed. Results. Between 8/2005 and 8/2008, 14 adults were managed for primary choledochal cyst disease. The average age was 41 years (range 17–86) and 79% were female. Presentations included biliary sepsis (3), pancreatitis (2), abdominal pain (3), or painless jaundice (1). Three patients had the cyst found during laparoscopic cholecystectomy, and two had an incidental finding after CT scan for an unrelated issue. The length of stay for those who had the cyst removed was 7.8 days (range 5–11). There were no operative or post-operative complications. Conclusions. Over the last 3 years 36% of our patients with choledochal cysts presented after incidental finding, either during a laparoscopic operation or after a CT scan for an unrelated problem. Increasing utilization of laparoscopy and CT scan for abdominal complaints has lead to a change in the pattern of presentation

Yttrium-90 Radioembolization for Colorectal Cancer Liver Metastases: A Single Institution Experience

Purpose. We sought to evaluate our experience using yttrium-90 (90Y) resin microsphere hepatic radioembolization as salvage therapy for liver-dominant metastatic colorectal cancer (mCRC). Methods. A retrospective review of consecutive patients with unresectable mCRC who were treated with 90Y after failing first and second line systemic chemotherapy. Demographics, treatment dose, biochemical and radiographic response, toxicities, and survival were examined. Results. Fifty-one patients underwent 90Y treatments of which 69% were male. All patients had previously undergone extensive chemotherapy, 31% had undergone previous liver-directed therapy and 24% had a prior liver resection. Using RECIST criteria, either stable disease or a partial response was seen in 77% of patients. Overall median survival from the time of first 90Y treatment was 10.2 months (95% CI = 7.5–13.0). The absence of extrahepatic disease at the time of treatment with 90Y was associated with an improved survival, median survival of 17.0 months (95% CI = 6.4–27.6), compared to those with extrahepatic disease at the time of treatment with 90Y, 6.7 months (95% CI = 2.7–10.6 Conclusion: 90Y therapy is a safe locoregional therapy that provides an important therapeutic option to patients who have failed first and second line chemotherapy and have adequate liver function and performance status

Transcatheter Arterial Chemoembolization Is a Feasible Palliative Locoregional Therapy for Breast Cancer Liver Metastases

Background. Liver metastases are common in advanced breast cancer. We sought to evaluate the role of transcatheter arterial chemoembolization (TACE) in breast cancer patients with hepatic metastases. Methods. A retrospective review of ten patients with breast cancer who were treated with TACE for unresectable liver metastases (1998–2008). Results. All patients, median age 46.5, had received prior systemic chemotherapies. Adriamycin was administered for 6, cisplatin/gemcitabine for 2, cisplatin for one and oxaliplatin for one patient. Median number of TACE cycles was 4. Kaplan Meier survival analysis showed an increase in median survival for patients who responded to treatment when compared to those who did not respond (24 vs 7 months, P = .02). Conclusions. This is one of the largest series of breast cancer patients with liver metastases treated with TACE. It suggests that TACE is a feasible palliative option and warrants further investigations

Rho-Regulatory Proteins in Breast Cancer Cell Motility and Invasion

The importance of the Rho-GTPases in cancer progression, particularly in the area of metastasis, is becoming increasingly evident. This review will provide an overview of the role of the Rho-regulatory proteins in breast cancer metastatis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44220/1/10549_2004_Article_5264599.pd

Cholangiocarcinoma risk factors and the potential role of aspirin

Choi et al. are to be congratulated on their work that adds to an already abundant literature on the topic of aspirin and cancer prevention. However, the retrospective design of the study, as well as the relative lack of detailed data on dosing, duration of usage, and concomitant other medications, do not allow for definitive evidence to support routine recommendations for daily aspirin usage. In an era of individualized medicine, future, prospective trials should aim to identify those subsets of patients who might benefit the most from aspirin usage, as well as further delineate the underlying mechanism of action related to this potential chemopreventative approach

Surgical Treatment of Peritoneal Carcinomatosis from Gastric Cancer

Peritoneal carcinomatosis from gastric cancer is considered a fatal disease with limited treatment options. Recent advances in the understanding of the disease process, systemic chemotherapy, and application of cytoreductive surgery and hyperthermic chemoperfusion have shown promising results in the management of this difficult disease. Novel therapies such as extensive intraperitoneal lavage and intraperitoneal targeted agents are being applied in the management of this disease. We review the current literature in this field and describe the rationale behind some of these advances