Soo-Teik Lee

The Clinical Outcomes of Transcatheter Microcoil Embolization in Patients with Active Lower Gastrointestinal Bleeding in the Small Bowel

Objective To assess the clinical outcomes of the transcatheter microcoil embolization in patients with active lower gastrointestinal (LGI) bleeding in the small bowel, as well as to compare the mortality rates between the two groups based on the visualization or non-visualization of the bleeding focus determined by an angiography. Materials and Methods We retrospectively evaluated all of the consecutive patients who underwent an angiography for treatment of acute LGI bleeding between January 2003 and October 2007. In total, the study included 36 patients who underwent a colonoscopy and were diagnosed to have an active bleeding in the LGI tracts. Based on the visualization or non-visualization of the bleeding focus, determined by an angiography, the patients were classified into two groups. The clinical outcomes included technical success, clinical success (no rebleeding within 30 days), delayed rebleeding (> 30 days), as well as the major and minor complication rates. Results Of the 36 patients, 17 had angiography-proven bleeding that was distal to the marginal artery. The remaining 19 patients did not have a bleeding focus based on the angiography results. The technical and clinical success rates of performing transcatheter microcoil embolizations in patients with active bleeding were 100% and 88%, respectively (15 of 17). One patient died from continued LGI bleeding and one patient received surgery to treat the continued bleeding. There was no note made on the delayed bleeding or on the major or minor complications. Of the 19 patients without active bleeding, 16 (84%) did not have recurrent bleeding. One patient died due to continuous bleeding and multi-organ failure. Conclusion The superselective microcoil embolization can help successfully treat patients with active LGI bleeding in the small bowel, identified by the results of an angiography. The mortality rate is not significantly different between the patients of the visualization and non-visualization groups on angiography.

Polyurethane-Covered Self-expandable Nitinol Stent for Malignant Biliary Obstruction: Preliminary Results

Purpose: To evaluate the immediate and long-term results in ten patients with malignant biliary obstruction using a polyurethane-covered, self-expandable nitinol stent. Methods: A nitinol stent, fully covered with high-elasticity polyurethane, with an unconstrained diameter of 10 mm and a total length of 60–80 mm, was placed transhepatically under fluoroscopic guidance in ten patients. The length of the biliary obstruction varied between 30–50 mm. The follow-up examination included a clinical assessment, serum bilirubin measurement, and ultrasound examinations at one-month intervals in all patients. Results: Initial stent deployment was successful in eight patients. Two patients experienced proximal migration, which was solved by insertion of two, uncovered Wallstents. One patient had the stent removed after two weeks because of severe nausea and vomiting. One patient had delayed migration of the covered stent after 40 weeks. The follow-up duration was 3–40 weeks (Mean: 16.9 weeks). Seven patients died (3–26 weeks) and three patients survived (24–40 weeks). The bilirubin measurements in all patients had significantly decreased one week after stent insertion. The levels of amylase and lipase had did not increase after stent insertion. Conclusions: A polyurethane-covered, self-expandable nitinol stent can be used effectively and safely in the treatment of malignant biliary obstruction. The preliminary results are favorable, but there is a need for further large studies to determine both long-term survival and patency.

The association of eotaxin-2 and eotaxin-3 gene polymorphisms in a Korean population with ulcerative colitis

The eotaxin gene family (eotaxin, eotaxin-2 and eotaxin-3) have been implicated in the recruitment of eosinophils, basophiles and helper T (Th) 2 lymphocytes that is a central aspect of allergic disease. We previously suggested that Eo2+179T>C and Eo2 +275C>T of the eotaxin-2, and Eo3 +2497T>G of the eotaxin-3 were significantly associated with susceptibility to asthma. To determine whether the single nucleotide polymorphisms (SNPs) of eotaxin-2 and eotaxin-3 gene family are associated with the susceptibility of ulcerative colitis (UC), we analyzed the genotype of 119 patients with UC and 303 controls using single-base extension (SBE) method. We also calculated the haplotype frequencies among Eo2 +179T>C and Eo2 +275C >T of the eotaxin-2 and Eo3 +2497T>G of the eotaxin-3 in both control and UC patients. The genotype frequency of Eo2 +179T>C and Eo2 +275C>T between UC patients and controls were significantly different (P=0.006 and 0.022, respectively). The genotype and allele frequencies of EoA2497T>G in UC patients were not significantly different from those in the controls without UC patients. Our results suggest that Eo2 +179T>C and Eo2 +275C>T of eotaxin-2 might be associated with the susceptibility of UC.

Parthenolide exerts inhibitory effects on angiogenesis through the downregulation of VEGF/VEGFRs in colorectal cancer

Parthenolide (PT) is responsible for the bioactivities of feverfew (Tanacetum parthenium). Apart from its potent anti-inflammatory effects, this compound has been reported to induce apoptosis in various cancer cells. However, little is known about its role in the process of tumor angiogenesis. In the present study, we investigated the effects and potential mechanisms of action of PT on angiogenesis in human colorectal cancer (CRC). The anti-angiogenic effects of PT were evaluated in cultured human umbilical vein endothelial cells (HUVECs) and in the human CRC cell lines, HT-29, SW620 and HCT116. PT markedly inhibited vascular cell migration and capillary-like structure formation even at a dose which had not effects on cell viability. PT also suppressed the expression of angiogenic biomarker proteins [vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)1 and VEGFR2] in both the HUVECs and CRC cells. Additionally, PT effectively inhibited tumor neovascularization in a HT-29 xenograft model. These results indicate that PT suppresses angiogenesis by reducing the expression of VEGF and its receptors and may be a viable drug candidate in anti-angiogenesis therapies for human CRC.

Parthenolide Sensitizes Human Colorectal Cancer Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand through Mitochondrial and Caspase Dependent Pathway

Background/Aims Combination therapy utilizing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) in conjunction with other anticancer agents, is a promising strategy to overcome TRAIL resistance in malignant cells. Recently, parthenolide (PT) has proved to be a promising anticancer agent, and several studies have explored its use in combination therapy. Here, we investigated the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. Methods HT-29 cells (TRAIL-resistant) were treated with PT and/or TRAIL for 24 hours. The inhibitory effect on proliferation was detected using the 3-(4, 5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Annexin V staining, cell cycle analysis, and Hoechst 33258 staining were used to assess apoptotic cell death. Activation of an apoptotic pathway was confirmed by Western blot. Results Treatment with TRAIL alone inhibited the proliferation of HCT 116 cells in a dose-dependent manner, whereas proliferation was not affected in HT-29 cells. Combination PT and TRAIL treatment significantly inhibited cell growth and induced apoptosis of HT-29 cells. We observed that the synergistic effect was associated with misregulation of B-cell lymphoma 2 (Bcl-2) family members, release of cytochrome C to the cytosol, activation of caspases, and increased levels of p53. Conclusion Combination therapy using PT and TRAIL might offer an effetive strategy to overcome TRAIL resistance in certain CRC cells.

Parthenolide promotes apoptotic cell death and inhibits the migration and invasion of SW620 cells

Background/Aims Parthenolide (PT), a principle component derived from feverfew (Tanacetum parthenium), is a promising anticancer agent and has been shown to promote apoptotic cell death in various cancer cells. In this study, we focused on its functional role in apoptosis, migration, and invasion of human colorectal cancer (CRC) cells. Methods SW620 cells were employed as representative human CRC cells. We performed the MTT assay and cell cycle analysis to measure apoptotic cell death. The wound healing, Transwell migration, and Matrigel invasion assays were performed to investigate the effect of PT on cell migration/invasion. Western blotting was used to establish the signaling pathway of apoptosis and cell migration/invasion. Results PT exerts antiproliferative effect and induces apoptotic cell death of SW620 cells. In addition, PT prevents cell migration and invasion in a dose-dependent manner. Moreover, PT markedly suppressed migration/invasion-related protein expression, including E-cadherin, β-catenin, vimentin, Snail, cyclooxygenase-2, matrix metalloproteinase-2 (MMP-2), and MMP-9 in SW620 cells. PT also inhibited the expression of antiapoptotic proteins (Bcl-2 and Bcl-xL) and activated apoptosis terminal factor (caspase-3) in a dose-dependent manner. Conclusions Our results suggest that PT is a potential novel therapeutic agent for aggressive CRC treatment.

Abstract 789: Parthenolide sensitizes colorectal cancer cells to TRAIL-induced apoptosis by regulating mitochonrial pathway

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Combination therapy utilizing of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in conjunction with other anticancer agents, is a promising strategy to overcome TRAIL resistance in malignant cells. Recently, parthenolide (PT) has proved to be a promising anticancer agent, and several studies have explored its use in combination therapy. Here, we investigated the molecular mechanisms by which PT sensitizes colorectal cancer (CRC) cells to TRAIL-induced apoptosis. TRAIL inhibited HCT116 cell growth in a dose-dependent manner; however, this reduction did not occur in TRAIL resistant HT-29 cells with an even higher dose of TRAIL. A combination of PT with TRAIL significantly inhibited cell growth of TRAIL resistant HT-29 cells. Consistent with cell growth inhibition, apoptotic cell death was significantly increased by a combination of PT with TRAIL in both of HCT116 and HT-29 cells. Results of flow cytometry analysis demonstrated that TRAIL-sensitive HCT116 cells had much higher death receptor (DR) 5 than TRAIL-resistant HT-29 cells. Interestingly, treatment of PT and/or TRAIL did not affect DR4/DR5, these results indicate that the apoptotic effect of combination is death receptor-independent apoptosis. We observed that the synergistic effect was associated with Bcl-2 family members, p53 and cytochrome C. Moreover, activation of caspase -3, -8 and -9 was increased by combination treatment in both of TRAIL-resistant and -sensitive cells. These results suggest that PT sensitizes TRAIL-induced apoptosis via death receptor-independent and mitochondrial-dependent pathway. Combination treatment using PT and TRAIL might offer an effective strategy to overcome TRAIL resistance in certain CRC cells. Citation Format: Se Lim Kim, Sang-Wook Kim, Soo-Teik Lee, Seong Hun Kim, In Hee Kim, Seung Ok Lee, Dae Ghon Kim. Parthenolide sensitizes colorectal cancer cells to TRAIL-induced apoptosis by regulating mitochonrial pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 789. doi:10.1158/1538-7445.AM2014-789