Decursin induces apoptosis in glioblastoma cells, but not in glial cells via a mitochondria-related caspase pathway

Decursin is a major biological active component of Angelica gigas Nakai and is known to induce apoptosis of metastatic prostatic cancer cells. Recently, other reports have been commissioned to examine the anticancer activities of this plant. In this study, we evaluated the inhibitory activity and related mechanism of action of decursin against glioblastoma cell line. Decursin demonstrated cytotoxic effects on U87 and C6 glioma cells in a dose-dependent manner but not in primary glial cells. Additionally, decursin increased apoptotic bodies and phosphorylated JNK and p38 in U87 cells. Decursin also down-regulated Bcl-2 as well as cell cycle dependent proteins, CDK-4 and cyclin D1. Furthermore, decursin-induced apoptosis was dependent on the caspase activation in U87 cells. Taken together, our data provide the evidence that decursin induces apoptosis in glioblastoma cells, making it a potential candidate as a chemotherapeutic drug against brain tumor.

MPTP-induced vulnerability of dopamine neurons in A53T α-synuclein overexpressed mice with the potential involvement of DJ-1 downregulation

Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the α-synuclein (α-syn) gene. Mutant α-syn expression increases the vulnerability of neurons to exogenous insults. In this study, we developed a new PD model in the transgenic mice expressing mutant hemizygous (hemi) or homozygous (homo) A53T α-synuclein (α-syn Tg) and their wildtype (WT) littermates by treatment with sub-toxic (10 mg/kg, i.p., daily for 5 days) or toxic (30 mg/kg, i.p., daily for 5 days) dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tyrosine hydroxylase and Bcl-2 levels were reduced in the α-syn Tg but not WT mice by sub-toxic MPTP injection. In the adhesive removal test, time to remove paper was significantly increased only in the homo α-syn Tg mice. In the challenging beam test, the hemi and homo α-syn Tg mice spent significantly longer time to traverse as compared to that of WT group. In order to find out responsible proteins related with vulnerability of mutant α-syn expressed neurons, DJ-1 and ubiquitin enzyme expressions were examined. In the SN, DJ-1 and ubiquitin conjugating enzyme, UBE2N, levels were significantly decreased in the α-syn Tg mice. Moreover, A53T α-syn overexpression decreased DJ-1 expression in SH-SY5Y cells. These findings suggest that the vulnerability to oxidative injury such as MPTP of A53T α-syn mice can be explained by downregulation of DJ-1.

Clinicopathological Characteristics of Ovarian Metastasis from Colorectal Cancer

PURPOSE: Treatment of ovarian metastasis from colorectal cancer has been controversial. We investigated the clinicopathologic features and treatment outcomes of patients with ovarian metastasis from colorectal carcinoma. METHODS: From January 1996 to May 2009, 567 women were treated for colorectal cancer. Of those, 23 patients were diagnosed as having ovarian metastasis. We reviewed 19 pathologically proven cases, retrospectively. RESULTS: The incidence of ovarian metastasis was 4.0%. The number of cases involving synchronous ovarian metastases was 9 (47.4%), and 10 cases (52.6%) involved metachronous ovarian metastases. Thirteen patients had metastases located in the pelvis and 6 also had peritoneal dissemination in addition to the ovarian metastasis. Twenty (63.1%) were treated with grossly complete resection. After a median follow-up duration of 45 months (range of 6~96 months), the median survival after the diagnosis of ovarian metastasis was 40 months. The median overall survival was significantly longer in the grossly complete resection group (48.5 vs. 16 months; P=0.001). For median survival after the diagnosis of ovarian-metastasis, patients with grossly complete resection showed a significantly more favorable survival rate than the group with remnant tumors (46.5 vs 9 months; P=0.009). The survival of patients with metastases located in the pelvis was better than the group with peritoneal dissemination. CONCLUSION: Grossly complete resection would be of help to improve the prognosis in selective patients with metastasis from colorectal cancer, especially when metastasis is located in the pelvis.

Intestinal Malrotation with Concurrent Portal Vein and Superior Mesenteric Vein Thromboses

Intestinal malrotation with volvulus is generally presented as a bilious vomiting and acute intestinal obstruction in the newborn period. It could compromise vascular supply of the small bowel secondary to torsion of superior mesenteric artery (SMA) and without urgent surgical management, it could lead to detrimental outcomes such as transmural bowel infarction and sepsis. However, in chronic cases, it is rarely obstructs the vascular supply and propagates to an acute bowel infarction. Rarely, chronic malrotation with midgut volvulus may not reduce the mesenteric blood supply because of collateral vessels, and the chronically stagnated blood flow of the superior mesenteric vein (SMV) favors thrombus formation within the lumen. The recommended treatment is Ladd's procedure and anticoagulation therapy. The authors present an unusual case of intestinal malrotation with chronic volvulus resulting in superior mesenteric vein and portal vein thrombosis in a 28-year-old patient.

A Case of Successful Percutaneous Drainage of a Pelvic Abscess Complicating Colonoscopy

Perforations that occur during colonoscopy are usually managed by surgical repair. When the patient's symptoms are mild and laboratory findings show minor abnormalities, a conservative treatment can be considered. Although an operation is the treatment of choice in patients with generalized peritonitis, in some selected patients, percutaneous abscess drainage can be an alternative to surgical intervention for drainage of deep-infected fluid collections or can act as a temporary measure until the patient becomes sufficiently stable for surgery. We report here on a 53-yr-old male patient who developed signs of localized peritonitis and had a pelvic abscess due to a colonic perforation after colonoscopy and was treated successfully by using percutaneous abscess drainage.

The Prognostic Significance of Tumor Budding, Tumor Nodules, and Lymph Node Extracapsular Extension in Stage III Colorectal Cancer Patients

PURPOSE: The prognosis of advanced colorectal cancer patients may be different even for the same TNM staging. The characteristic features of tumors, such as tumor budding, tumor nodules, and extracapsular extension (ECE) of lymph nodes, can influence the disease progression and the outcome for patients. Tumor budding occurs what at the invasion front of colorectal adenocarcinomas, tumor cells, singly or in small aggregates, become detached from the neoplastic glands, and it can be divided it into two groups, low grade (0~16 foci in a field) and high grade (17 or more foci in a field). A tumor nodule is histologically identified within the fatty tissue or the detached fatty tissue around the dissected lymph nodes, or is a place picked up as lymph nodes from resected specimens which contain no lymph node components. ECE is defined as a tumor extension beyond the node capsule. The aims of this study were to evaluate the clinical significance of tumor budding, tumor nodules, and ECE of lymph nodes as prognostic factors in Stage III colorectal cancer patients. METHODS: We analyzed the disease-free and overall 5-year survival rates and recurrence rates in 94 Stage-III colorectal cancer patients according to tumor the budding intensity, the tumor nodules, and the lymph node ECE status. RESULTS: Of the entire group, the 5-year disease-free and overall survival rates were 49%, and 50%, respectively. The 5-year disease-free and overall survival rates were higher in the low-grade tumor budding group than in the high-grade group (58% vs 33%, P=0.045, 61% vs 39%, P=0.003). The 5-year disease-free and overall survival rates in patients with tumor nodules were lower than those in patients without one (44% vs 69%, P=0.086, 47% vs 77%, P=0.018). The recurrence rate was also higher in the group with tumor nodules than without one (80% vs 52%, P=0.045). The 5-year disease-free and overall survival rates were higher in the ECE negative group than in the positive one (68% vs 37%, P=0.018, 75% vs 42%, P=0.001). The recurrence rate was also higher in the ECE positive group than in the negative group (78% vs 46%, P=0.008). The existence of ECE and tumor nodule were strongly related to systemic recurrence (P=0.006, P=0.033), but not to the local recurrence (P=0.777, P=0.611). Considering the analysis of the recurrence pattern by N stage classification, there is no statistical difference in the N2 patient group, but there was in the existence of ECE and tumor nodule were strongly related to the systemic recurrence in N1 group (P=0.019, P=0.028). These three factors were scored according to the existence, and the score range was divided into two prognostic groups, high risk group (> or =2) and low risk group (<2). The high risk group was significantly associated with systemic recurrence (P= 0.004) rather than recurrence (P=0.865), and these score value were only significant in the N1 patient group (P=0.007) rather than in the N2 group (P=0.927). The high risk group also showed poor overall survival rate compared with the low risk one in only the N1 group (P=0.002), but nof in the N2 group (P=0.193). On multivariate analysis, UICC stage and ECE were two significant factors for tumor recurrence and the 5-year disease-free survival rate. CONCLUSIONS: These data showed that even if similar lymph node metastasis existed in advanced colorectal cancer patients, there was a different 5-year disease-free survival rate and overall survival rate according to the tumor budding, tumor nodule, and ECE status. On multivariate analysis, UICC stage and ECE were two significant factors for the tumor recurrence and the 5-year disease-free survival rate. Our results suggest that tumor budding, tumor nodule, and ECE of lymph node are excellent parameters to provide a confident prediction of clinical outcome.

Thymidylate Synthase Expression Using Immunohistochemical Staining in Colorectal Cancer

PURPOSE: Thymidylate synthase (TS) is a critical enzyme in the DNA synthesis and an important target of cancer chemotherapeutic agents, such as 5-fluorouracil (5-FU). Recent studies suggest that TS expression is related to the prognosis of various cancers and the mechanism of chmotherapeutic drug resistance. This retrospective study was performed to determine whether TS expressions in primary colorectal tumors influence the overall survival and recurrence for patients with colorectal cancer. METHODS: Intratumoral TS expression was evaluated by immunohistochemical staining using TS-106 monoclonal antibody in primary colorectal cancers of 64 patients who had undergone surgery from July, 1995 to June, 1999. The relationship between TS expressions and patients' survival was evaluated statistically. The median follow-up period was 25.7 months. RESULTS: Overall positive TS expression rate was relatively high (54.7%) in colorectal cancers, and overall disease-free survival rate was significantly higher in the TS positive group (P=0.0204). But there was no statistically significant differences in overall survival rates (P=0.249) and tumor recurrence rates (P=0.732) between positive TS group and negative TS group. CONCLUSIONS: These results suggest that TS expression status in the colorectal cancer tissue is only related to the overall disease-free survival rates, not the overall survival rates and tumor recurrence rates. More objective method and long term follow up study will be required for accurate assessment of clinical importance of TS expression in colorectal cancers.

Microsatellite Instability and hMSH2 Gene Mutations in Sporadic Colorectal Cancers

Microsatellites are short nucleotide repeat sequences present throughout the human genome. Alterations of microsatellites, comprising extra or missing copies of these se quences, have been termed microsatellite instability(MSI, genetic instability, replication errors, RER(+) phenotype). To date, at least four genes involved in DNA mismatch repair, hMSH2, hMLH1, hPMS1 and hPMS2, are thought to account for the observation of microsatellite instability in tumor from Hereditary nonpolyposis colorectal cancer (HNPCC) patients. The genetic defect responsible for the MIN+ phenotype in sporadic colorectal cancer, however, has yet to be clearly delineated. The purpose of this study was to determine the presence of MSI in sporadic cancer and to correlate its occurrence with clinicopathological parameters, we have studied six microsatellite loci by use of polymerase chain reaction amplification and denaturing polyacrylamide gel electrophoresis. We found that 20%(9 of 46 cases) sporadic colorectal cancers showed RER at two or several loci(RER+). Microsatellite instability was associated with location of the tumor in the proximal colon 66%(6 of 9 cases) and with poorly differentiated tumor phenotype 56%(5 of 9 cases). In order to better understand the role of somatic alterations within hMSH2 in the process of colorectal tumorigenesis, we examined the most conserved regions(codon 598~789) of this gene in nine patients with MIN spotadic colorectal cancer. 6 patient of RER(+) colorectal ca. patients had a polymorphism which was a T to C base change in the intron sequence at -6 position of the splice acceptor site at the 5'end of exon 13. This particular sequence variation is a polymorphism rather than a mutation which increase cancer susceptability. These data suggest that the genetic instability is detect ed in some colorectal cancers and play an important role in the pathogenesis of sporadic colorectal cancer.