• Journal of Digestive Cancer Research
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• v.4 no.2
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• pp.64-76
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• 2016

The step-wise process of colorectal carcinogenesis from aberrant crypt foci, adenoma to adenocarcinoma, is relatively suitable for chemopreventive intervention. Accumulated evidences have revealed that maintaining an undifferentiated state (stemness), inflammation, and oxidative stress play important roles in this colon carcinogenesis process. However, appropriate molecular targets that are applicable to chemopreventive intervention regarding those three factors are still unclear. In this review, we summarized appropriate molecular targets by identification and validation of the prospective targets from a comprehensive overview of data that showed colon cancer preventive effects in clinical trials, epidemiological studies and basic research. We first selected a study that used aspirin, statins and metformin from FDA approved drugs, and epigallocatechin-gallate and curcumin from natural compounds as potential chemopreventive agents against colon cancer because these agents are considered to be promising chemopreventive agents. Experimental and observational data revealed that there are common target molecules in these potential chemopreventive agents: T-cell factor/lymphoid enhancer factor (TCF/LEF), nuclear factor-&B (NF-κB) and nuclear factor-erythroid 2-related factor 2(NRF2). Moreover, these targets, TCF/LEF, NF-κB and NRF2, have been also indicated to suppress maintenance of the undifferentiated state, inflammation and oxidative stress, respectively. In the near future, novel promising candidate agents for colon cancer chemoprevention could be identified by integral evaluation of their effects on these three transcriptional activities.

• Molecules and Cells
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• v.44 no.10
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• pp.710-722
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• 2021

Hypoxia, or low oxygen tension, is a hallmark of the tumor microenvironment. The hypoxia-inducible factor-1α (HIF-1α) subunit plays a critical role in the adaptive cellular response of hypoxic tumor cells to low oxygen tension by activating gene-expression programs that control cancer cell metabolism, angiogenesis, and therapy resistance. Phosphorylation is involved in the stabilization and regulation of HIF-1α transcriptional activity. HIF-1α is activated by several factors, including the mitogen-activated protein kinase (MAPK) superfamily. MAPK phosphatase 3 (MKP-3) is a cytoplasmic dual-specificity phosphatase specific for extracellular signal-regulated kinase 1/2 (Erk1/2). Recent evidence indicates that hypoxia increases the endogenous levels of both MKP-3 mRNA and protein. However, its role in the response of cells to hypoxia is poorly understood. Herein, we demonstrated that small-interfering RNA (siRNA)-mediated knockdown of MKP-3 enhanced HIF-1α (not HIF-2α) levels. Conversely, MKP-3 overexpression suppressed HIF-1α (not HIF-2α) levels, as well as the expression levels of hypoxia-responsive genes (LDHA, CA9, GLUT-1, and VEGF), in hypoxic colon cancer cells. These findings indicated that MKP-3, induced by HIF-1α in hypoxia, negatively regulates HIF-1α protein levels and hypoxia-responsive genes. However, we also found that long-term hypoxia (>12 h) induced proteasomal degradation of MKP-3 in a lactic acid-dependent manner. Taken together, MKP-3 expression is modulated by the hypoxic conditions prevailing in colon cancer, and plays a role in cellular adaptation to tumor hypoxia and tumor progression. Thus, MKP-3 may serve as a potential therapeutic target for colon cancer treatment.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.24 no.2
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• pp.135-144
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• 2021

Purpose: Although ultrasonography is the gold standard of diagnosing intussusception, plain abdomen radiograph (AXR) is often used to make differential diagnosis for pediatric patients with abdominal pain. In intussusception patients, we aimed to analyze the AXR and clinical data to determine the characteristics of early AXR findings associated with diagnosis of intussusception and recurrence after reduction. Methods: Between January 2011 and June 2018, 446 patients diagnosed with intussusception based on International Classification of Diseases-10 code of K56.1 were admitted. We retrospectively reviewed medical records of 398 patients who received air reduction; 51 of them have recurred after initial reduction. We evaluated six AXR features including absent ascending colon gas, absent transverse colon gas, target sign, meniscus sign, mass, and ileus. Clinical data and AXR features were compared between single episode and recurrence groups. Results: Two groups did not show significant differences regarding clinical data. Mean time to recurrence from air reduction was 3.4±3.2 days. Absent ascending colon gas (63.9%) was the most common feature in intussusception, followed by mass (29.1%). All of six AXR features were observed more frequently in the recurrence group. Absent transverse colon gas was the most closely associated AXR finding for recurrence (odds ratio, 2.964; 95% confidence interval, 1.327-6.618; p=0.008). Conclusion: In our study, absence of ascending colon gas was the most frequently seen AXR factor in intussusception patients. Extended and careful observation after reduction may be beneficial if such finding on AXR is found in intussusception patients.

• Journal of Integrative Natural Science
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• v.16 no.3
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• pp.81-95
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• 2023

Colorectal cancer is one of the most common types of cancer worldwide, ranking third after lung and breast cancer in terms of global prevalence. With an expected 1.93 million new cases and 935,000 deaths in 2020, it is more prevalent in males than in women. Evidence has shown that during the later stages of colon cancer, STAT1 promotes tumor progression by promoting cell survival and resistance to chemotherapy. Recent studies have shown that inhibiting STAT1 pathway leads to a reduction in tumor cell proliferation and growth, and can also promote apoptosis in colon cancer cells. One of the recent approaches in the field of drug discovery is drug repurposing. In drug repurposing approach we have virtually screened FDA database against STAT1 protein and their interactions have been studied through Molecular docking. Cross docking was performed with the top 10 compounds to be more specific with STAT1 comparing the affinity with STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6. The drugs that showed higher affinity were subjected to Conceptual - Density functional theory. Besides, the Molecular dynamic simulation was also carried out for the selected leads. We also validated in-vitro against colon cancer cell lines. The results showed mainly Acetyldigitoxin has shown better binding to the target. From this study, we can predict that the drug Acetyldigitoxin has shown noticeable inhibitory efficiency against STAT1, which in turn can also lead to the reduction of tumor cell growth in colon cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.5
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• pp.2061-2068
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• 2015

Background: Tumors are largely unable to metabolize ketone bodies for energy due to various deficiencies in one or both of the key mitochondrial enzymes, which may provide a rationale for therapeutic strategies that inhibit tumor growth by administration of a ketogenic diet with average protein but low in carbohydrates and high in fat. Materials and Methods: Thirty-six male BALB/C nude mice were injected subcutaneously with tumor cells of the colon cancer cell line HCT116. The animals were then randomly split into three feeding groups and fed either a ketogenic diet rich in omega-3 fatty acids and MCT (MKD group; n=12) or lard only (LKD group; n=12) or a standard diet (SD group; n=12) ad libitum. Experiments were ended upon attainment of the target tumor volume of $600mm^3$ to $700mm^3$. The three diets were compared for tumor growth and survival time (interval between tumor cell injection and attainment of target tumor volume). Results: The tumor growth in the MKD and LKD groups was significantly delayed compared to that in the SD group. Conclusions: Application of an unrestricted ketogenic diet delayed tumor growth in a mouse xenograft model. Further studies are needed to address the mechanism of this diet intervention and the impact on other tumor-relevant parameters such as invasion and metastasis.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.6
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• pp.391-397
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• 2010

E2F transcription factors and their target genes have been known to play an important role in cell growth control. We found that curcumin, a polyphenolic phytochemical isolated from the plant Curcuma longa, markedly suppressed E2F4 expression in HCT116 colon cancer cells. Hydrogen peroxide was also found to decrease E2F4 protein level, indicating the involvement of reactive oxygen species (ROS) in curucmin-induced downregulation of E2F4 expression. Involvement of ROS in E2F4 downregulation in response to curcumin was confirmed by the result that pretreatment of cells with N-acetylcystein (NAC) before exposure of curcumin almost completely blocked the reduction of E2F4 expression at the protein as well as mRNA level. Anti-proliferative effect of curcumin was also suppressed by NAC which is consistent to previous reports showing curcumin-superoxide production and induction of poly (ADP-ribose) polymerase (PARP) cleavage as well as apoptosis. Expression of several genes, cyclin A, p21, and p27, which has been shown to be regulated in E2F4-dependent manner and involved in the cell cycle progression was also affected by curcumin. Moreover, decreased (cyclin A) and increased (p21 and p27) expression of these E2F4 downstream genes by curcumin was restored by pretreatment of cells with NAC and E2F4 overexpression which is induced by doxycycline. In addition, E2F4 overexpression was observed to partially ameliorate curcumin-induced growth inhibition by cell viability assay. Taken together, we found curcumin-induced ROS down-regulation of E2F4 expression and modulation of E2F4 target genes which finally lead to the apoptotic cell death in HCT116 colon cancer cells, suggesting that E2F4 appears to be a novel determinant of curcumin-induced cytotoxicity.

• Journal of Photoscience
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• v.10 no.3
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• pp.237-240
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• 2003

The tetradecameric peptide (K47-K60) near the NH$_2$-terminal region of epithelial-cell adhesion molecule (Ep-CAM) was chosen as antigenic site and a polyclonal antibody was generated, which could recognize Ep-CAM from the mouse colon tissue or the colon cancer cell, CT-26, in Western blot analysis. Then, the fluorescein isothiocyanate (FITC), a fluorescence dye, was conjugated with the affinity purified Ep-CAM antibody using thiocyanate and the amino groups of FITC and antibody, respectively. The molar ratio of FITC to antibody was estimated approximately 1.86 to 1.00 by measuring the optical densities at 492 nm and 280 nm. Ep-CAM antibody-FITC conjugate was then used for immunohistochemistry of the CT-26 cells. Judging from the shapes formed by fluorescence, the Ep-CAM antibody could delivered FITC to the surface of cells in which Ep-CAM was expressed. This result implies that Ep-CAM antibody could be also used for the tissue-specific delivery of the photosensitizer to the target protein via antigen-antibody interaction.

• Genomics & Informatics
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• v.9 no.4
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• pp.173-180
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• 2011

Recent trends in generating multiple, large-scale datasets provide new challenges to manipulating the relationship of different types of components, such as gene expression and drug response data. Integrative analysis of compound response and gene expression datasets generates an opportunity to capture the possible mechanism of compounds by using signature genes on diverse types of cancer cell lines. Here, we integrated datasets of compound response and gene expression profiles on NCI60 cell lines and constructed a network, revealing the relationship for 801 compounds and 341 gene probes. As examples, obtusol, which shows an exclusive sensitivity on a small number of colon cell lines, is related to a set of gene probes that have unique overexpression in colon cell lines. We also found that the SLC7A11 gene, a direct target of miR-26b, might be a key element in understanding the action of many diverse classes of anticancer compounds. We demonstrated that this network might be useful for studying the mechanisms of varied compound response on diverse cancer cell lines.

• Journal of Veterinary Clinics
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• v.25 no.6
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• pp.549-552
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• 2008

An eight-month-old, intact female Jindo, weighing 9 kg with a one-day history of acute bloody diarrhea was referred. Plain abdominal radiographic findings included evidence of a soft tissue tubular mass within the dilated colon. In ultrasonographs, a target-like mass was identified with multiple hyperechoic and hypoechoic parallel wall layers. A barium enema showed a large radiolucent filling defect within the colon and a completely occlusive lumen. On the basis of these images, ileocecocolic and colocolic intussusception was diagnosed. Surgical manual reduction, resection and anastomosis were performed. The patient recovered normally without any complications or recurrence.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.9
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• pp.3981-3986
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• 2014

Ganoderma lucidum polysaccharides (GLP) extracted from Ganoderma lucidum have been shown to induce cell death in some kinds of cancer cells. This study investigated the cytotoxic and apoptotic effect of GLP on HCT-116 human colon cancer cells and the molecular mechanisms involved. Cell proliferation, cell migration, lactate dehydrogenase (LDH) levels and intracellular free calcium levels ($[Ca^{2+}]i$) were determined by MTT, wound-healing, LDH release and fluorescence assays, respectively. Cell apoptosis was observed by scanning and transmission electron microscopy. For the mechanism studies, caspase-8 activation, and Fas and caspase-3 expression were evaluated. Treatment of HCT-116 cells with various concentrations of GLP (0.625-5 mg/mL) resulted in a significant decrease in cell viability (P< 0.01). This study showed that the antitumor activity of GLP was related to cell migration inhibition, cell morphology changes, intracellular $Ca^{2+}$ elevation and LDH release. Also, increase in the levels of caspase-8 activity was involved in GLP-induced apoptosis. Western blotting indicated that Fas and caspase-3 protein expression was up-regulated after exposure to GLP. This investigation demonstrated for the first time that GLP shows prominent anticancer activities against the HCT-116 human colon cancer cell line through triggering intracellular calcium release and the death receptor pathway.