Antiproliferative effect of 1α,25-dihydroxyvitamin D3 involves upregulation of cyclin-dependent kinase inhibitor p21 in human pancreatic cancer cells.

BACKGROUND/AIMS: The aim of this study was to investigate the effect of 1α,25-dihydroxyvitamin D3 on proliferation of human pancreatic cancer cell lines and to identify related cell cycle regulatory proteins with antiproliferative effects. METHODOLOGY: Human pancreatic cancer cell lines SUIT-2 and its four sublines, and Panc-1, AsPC-1, and MiaPaCa-2 were treated with1α,25-dihydroxyvitamin D3. The number of cells was measured by the MTT method, and the cell cycle regulatory proteins were then analyzed by Western blotting. RESULTS: Eight human pancreatic cancer cell lines expressed vitamin D receptor (VDR) mRNA. 1α,25-dihydroxyvitamin D3 inhibited proliferation of SUIT-2 and its sublines. We found p21 to be upregulated after 24 hours in S2-028, the cell line in which proliferation was most inhibited by 1α,25-dihydroxyvitamin D3. CONCLUSIONS: 1α,25-dihydroxyvitamin D3 inhibited proliferation of pancreatic cancer cells and is involved in the upregulation of cyclin-dependent kinase inhibitor p21.

Thrombin stimulates integrin ß1-dependent adhesion of human pancreatic cancer cells to vitronectin through protease-activated receptor (PAR)-1.

BACKGROUND/AIMS: The aim of this study was to investigate the effect of thrombin and the thrombin receptor protease-activated receptor (PAR)-1 on adhesion of human pancreatic cancer cell lines to extracellular matrices (ECMs) and to identify related integrins with these effects. METHODOLOGY: Human pancreatic cancer cell lines SUIT-2 and its four sublines, and Panc- 1, AsPC-1 and MiaPaCa-2 were treated with thrombin, PAR-1 agonist TRAP-6, PAR-1 antagonist SCH79797, or anti-integrin ±vß3, ±vß5 and ß1 monoclonal antibodies. Cells were incubated for 45 minutes on micro titer plates that were pre-coated with ECMs (fibronectin, laminin, vitronectin, type IV collagen). The number of adherent cells was measured by the MTT method. RESULTS: Eight human pancreatic cancer cell lines expressed PAR-1. Thrombin significantly enhanced adhesion of SUIT-2 and its sublines and MiaPaCa-2 to vitronectin, especially in the SUIT-2 subline S2-007. We obtained similar results on S2-007 cells through treatment with TRAP-6. However, SCH79797 inhibited the effect of thrombin. Furthermore, anti-integrin ß1 antibody conspicuously inhibited 1U/mL thrombin-induced enhancement of adhesion to vitronectin. CONCLUSIONS: Thrombin significantly enhanced adhesion of pancreatic cancer cells to vitronectin through PAR- 1 depending on the presence of integrin ß1. Suppression of thrombin action by anti-integrin ß1 antibody will become a useful therapy against pancreatic cancer.

Differential expression of organic anion transporters in rats subjected to 70% or 90% hepatectomy.

BACKGROUND/AIMS: Differences in hepatic organic anion transporters were compared in rats to identify a causative factor for early stage acute hepatic failure after 70% or 90% hepatectomy (Hx). METHODOLOGY: Male Wistar rats (8 weeks, 250-330g) were randomly assigned to one of two groups for 70% Hx or 90% Hx, and sacrificed at 0, 6, 12, 24, 48, or 72 hours after Hx. Posthepatectomy expression of the bile salt export pump (Bsep), multidrug resistance proteins 2 and 3 (Mrp2, Mrp3), sodium-dependent taurocholate co-transporting polypeptide (Ntcp), and organic anion transporting polypeptides 1 and 2 (Oatp1, Oatp2) were analyzed by Northern blotting. Serum liver function tests were also performed. RESULTS: Postoperative survival rates at 72 hours after 70% and 90% Hx were 100% and 50%, respectively. mRNA expression of Bsep and Mrp3 was increased after 90% Hx, while decreased after 70% Hx. These values were significantly greater at 12 and 24 hours after 90% Hx than after 70% Hx (p < 0.05). In contrast, Mrp2 expression was downregulated to a half of the preoperative level after 90% Hx, while increased after 70% Hx. mRNA expression of uptake transporters (Ntcp, Oatp1, Oatp2) was decreased after 70% Hx and 90% Hx with a similar extent. Total serum bilirubin and bile acid levels were significantly increased after both hepatectomy procedures with a greater extent after 90% Hx. CONCLUSIONS: Alteration of mRNA expression of Bsep, Mrp2 and Mrp3 may be characteristic behavior in the early stage of acute liver failure.

Transarterial infusion chemotherapy with epirubicin in water-in-oil-in-water emulsion for recurrent hepatocellular carcinoma in the residual liver after hepatectomy.

PURPOSE: To evaluate the midterm results of transarterial infusion (TAI) with water-in-oil-in-water (W/O/W) emulsion containing an anticancer agent for patients with recurrent hepatocellular carcinoma (HCC) after surgical resection. MATERIALS AND METHODS: We retrospectively analyzed the results of TAI of W/O/W emulsion containing epirubicin for 18 consecutive patients with recurrent HCC after surgical resection. Fourteen patients were males and four were females; their ages ranged from 51 to 86 years (mean 69.8 years). TAI was repeated every 1-6 months based on the response of the tumor. A total of 41 TAI procedures were performed for 18 patients. Angiographically, recurrent HCC appeared a single nodule in nine patients and was multinodular in other nine patients. TAI was performed selectively in 27 procedures and non-selectively in 14 procedures. Maximum response within 3 months was rated as follows: a complete response (CR, complete disappearance of tumor and no evidence of new lesions); partial response (PR, a reduction of <50% in total volume of all tumors calculated from the two longest perpendicular diameters without a new lesion); no response (NC, a reduction of <50% in total volume or an increase of <25% without a new lesion); or progression of disease (PD, an increase of >25% in total volume or evidence of new lesions). Survival time was defined as the time from the date of first TAI to the date of death or last follow-up (median follow-up time: 17 months) and the survival curve was estimated using the Kaplan-Meier method. RESULTS: The CR rate was 33% and the effective response rate (CR rate+PR rate) was 78%. Survival from the time of initial TAI was 94% at 1 year, 76% at 2 years, and 76% at 3 years. CONCLUSIONS: TAI of W/O/W emulsion may be an effective treatment for patients with recurrent HCC after surgical resection.