Benzo[c]phenanthridine alkaloids fromCorydalis incisa

Six benzo[c]phenanthridine alkaloids, corynoline (1), acetylcorynoline (2), corynoloxine (3), luguine (4), 6-oxocorynoline (5), and 12-hydroxycorynoloxine (6) were isolated from the aerial parts of Corydalis incisa, and 6 was isolated for the first time from nature. The structure was elucidated by NMR techniques.     

Oral administration of benzyl-isothiocyanate inhibits solid tumor growth and lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice

Benzyl-isothiocyanate (BITC) is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables, and has also been shown to have anti-tumor properties. To evaluate the effects of BITC administration on the tumor growth and metastasis of breast cancer, 4T1 murine mammary carcinoma cells were injected into the inguinal mammary fat pads of syngeneic female BALB/c mice. One day later, the mice were subjected to gavage for 4 weeks with BITC (0, 5, or 10 mg/kg body weight/day). Oral BITC treatment induced a significant reduction in the growth of solid tumors. BITC reduced hemoglobin contents and CD31 and vascular endothelial growth factor (VEGF) expression in the tumors, as well as circulating levels of VEGF. Reduced expressions of proliferating cell nuclear antigen and cyclin-dependent kinase 4 were noted in the tumors of BITC-treated mice. BITC markedly increased the numbers of apoptotic cells with increased Bax expression, cleaved caspase-3, and PARP levels, but reduced Bcl-2 expression in tumor tissues. In addition, BITC was shown to reduce the numbers of pulmonary tumor nodules and the total pulmonary metastatic volume. BITC induced a significant reduction in the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and urokinase-type plasminogen activator in the sera and lungs of 4T1 cell-injected mice. However, the concentrations of TIMP-2 and plasminogen activator inhibitor-1 were increased in the sera and lungs of BITC-treated mice. The results of this study indicate that BITC has potential as a preventive agent for metastatic breast cancer.     

Validation of Western common recurrent chromosomal aberrations in Korean chronic lymphocytic leukaemia patients with very low incidence

In Asia, the incidence of chronic lymphocytic leukaemia (CLL) is lower than in Western countries. Only a few studies of CLL have been conducted in Korea, and no long‐term clinical outcome data are available. We assessed the frequency of common chromosomal aberrations in Korean CLL patients using interphase fluorescence in situ hybridization (FISH) and investigated their relationship to clinical outcomes. Between 2000 and 2011, conventional cytogenetic studies were performed in 58 patients, and FISH results were available in 48 patients. We used six DNA probes for the detection of del(13q14), trisomy 12, del(11q22), del(17p13), IGH rearrangement and del(6q23). Chromosomal aberrations were identified in 15 of 58 patients (26%) with conventional cytogenetic studies and in 25 of 48 patients (52%) with interphase FISH, including six patients with complex karyotypes. In contrast with the results of Western studies, trisomy 12 was the most common aberration, followed by IGH rearrangement, del(13q14), del(11q22) and del(17p13). Deletion of 6q23 was not observed, and isolated del(13q14) was less frequent than in Western studies. Compared with the other types of chromosomal aberrations, patients with del(11q22) and del(17p13) were more likely to be Rai stage 3–4 and Binet stage C, resulting in poor responses to chemotherapy and worse outcomes. In contrast, patient with trisomy 12 and isolated del(13q14) showed better responses and superior survival outcomes. The incidence of CLL is lower in Korea than in Western countries, and the frequency of chromosomal aberrations differs, perhaps reflecting differences in the pathogenic mechanism between ethnicities. Large prospective studies are needed to further assess the prognostic value of these results in Korean CLL patients. Copyright © 2013 John Wiley & Sons, Ltd.     

Effects of dietary factors and the NAT2 acetylator status on gastric cancer in Koreans

Environmental dietary carcinogens and genetic polymorphisms in metabolic enzymes have been reported to be the risk factors for gastric cancer. This study was undertaken to investigate the effects of the diet, the N‐acetyltransferase (NAT) 2 acetylation status and their interaction on gastric cancer risk. The study population consisted of 471 gastric cancer patients and 471 age‐ and sex‐matched control subjects. NAT2 genotypes were identified using single‐nucleotide primer extension reaction methods. Thirty‐one alleles related to 12 polymorphism sites were assayed in this study. Significantly increased odds ratios were observed in former smokers (OR = 2.39, 95% CI = 1.57–3.62), heavy drinkers (OR = 1.28, 95% CI = 1.06–1.55) and individuals who eat well‐done meat (OR = 1.24, 95% CI = 1.09–1.41). The odds ratios (95% CI) for high intake of kimchi, stews and soybean paste were 3.27 (2.44–4.37), 1.96 (1.50–2.58) and 1.63 (1.24–2.14), respectively. The NAT2 genotype alone was not associated with gastric cancer risk. A significant gene–environment interaction was observed between environmental carcinogens and NAT2 genotypes. The odds ratios for kimchi, stews and soybean paste were higher in slow/intermediate acetylators than in rapid acetylators. The odds ratios for slow/intermediate acetylators were 2.28 (95% CI: 1.29–4.04) for light smokers and 3.42 (95% CI: 2.06–5.68) for well‐done meat intake. The NAT2 acetylator genotype may be an important modifier of the effects of environmental factors on gastric cancer risk. © 2009 UICC     

Protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in acute myeloid leukemia.

INTRODUCTION: Protein kinase CK2 is implicated in cellular proliferation and transformation. However, the clinical and biological significances of CK2 have not been elucidated in acute myeloid leukemia (AML). EXPERIMENTAL DESIGN: We evaluated the biological significances of catalytic subunit of CK2 (CK2alpha) expression in leukemia cell lines and primary leukemic blasts obtained from AML patients. RESULTS: In this study, the expression of CK2alpha was elevated in a substantial proportion of AML. In AML patients with normal karyotype, the disease-free survival and overall survival rates were significantly lower in the CK2alpha-high compared with the CK2alpha-low AML cases (P=0.0252 and P=0.0392, respectively). An induced overexpression of CK2alpha increased the levels of Ser473 phosphorylated (p)-Akt/protein kinase B (PKB), p-PDK1, pFKHR, p-BAD, Bcl-2, Bcl-xL, Mcl-1, and XIAP. Treatment of U937 cell line and primary AML blasts with selective CK2 inhibitor, tetrabromobenzotriazole or apigenin, reduced the levels of these molecules in a dose-dependent manner. CK2alpha small interfering RNA treatment also resulted in a down-regulation of p-Akt/PKB and Bcl-2 in U937 cells. Apigenin-induced cell death was preferentially observed in the CK2alpha-high leukemia cell lines, HL-60 and NB4, which was accompanied by cytoplasmic release of SMAC/DIABLO and proteolytic cleavage of procaspase-9, procaspase-3, procaspase-8, and poly(ADP)ribose polymerase. An induced overexpression of CK2alpha potentially enhanced the sensitivity of U937 cells to the apigenin-induced cell death. Apigenin-induced cell death was significantly higher in CK2alpha-high AML compared with CK2alpha-low AML (P<0.0001) or normal bone marrow samples (P<0.0001). CONCLUSION: These findings strongly suggest protein kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in AML.