• The Korean Journal of Cytopathology
• /
• v.1 no.1
• /
• pp.111-120
• /
• 1990

Small cell neuroendocrine carcinoma of the uterine cervix is a distinct subtype of cervical cancer that appears analogous to oat cell carcinoma and carcinoid tumors of the lung. It has been assumed to be derived from the neural crest via argyrophilic cells in the normal endocervix. We have recently encountered a case of small cell neuroendocrine carcinoma of the uterine cervix coexisting with adenocarcinoma which was argyrophil negative. A 66-year-old multiparous woman was admitted because of vaginal bleeding for 2 months. Cervicovaginal smear revealed several scattered clusters and sheets of monotonous small cells with some peripheral palisading in the background of hemorrhage and necrosis. Radical hysterectomy specimen revealed an ulcerofungating tumor on endocervical canal which was composed of two components. Major component of the tumor was made up of monomorphic population of small oval-shaped tumor cells arranged in sheets and partly in acinar structures or trabecular fashion. Other component was adenocarcinoma, endocervical well-differentiated type. Argyrophilia was present on the Grimelius stain and immunohistochemical studies revealed diffuse positivity to neuron-specific enolase and carcinoembryonic antigen. Electron microscopic examination showed clusters of small round to oval cells, which had a few well-formed desmosomes and several membrane-bound, dense-core neurosectetory granules.

• Journal of Radiation Protection and Research
• /
• v.43 no.2
• /
• pp.66-74
• /
• 2018

Background: Tumor response to anticancer therapies can much be influenced by microenvironmental factors. In this study, we determined the effect of these microenvironmental factors on DNA methylation using A549 human lung adenocarcinoma cell line. Materials and Methods: We subjected A549 cells to various conditions mimicking tumor microenvironment including hypoxia, acidosis (sodium lactate), oxidative stress ($H_2O_2$), bystander effect (supernatant from doxorubicin (Dox)-treated or irradiated cells), and immune cell infiltration (supernatant from THP-1 or Jurkat T cells). Genomic DNA was isolated from these cells and analyzed for DNA methylation. Clonogenic cell survival, gene expression, and metabolism were analyzed in cells treated with some of these conditions. Results and Discussion: We found that DNA methylation level was significantly decreased in A549 cells treated with conditioned media from Dox-treated cells or Jurkat T cells, or sodium lactate, indicating an active transcription. To determine whether the decreased DNA methylation affects radiation sensitivity, we exposed cells to these conditions followed by 6 Gy irradiation and found that cell survival was significantly increased by sodium lactate while it was decreased by conditioned media from Dox-treated cells. We further observed that cells treated with conditioned media from Dox-treated cells exhibited significant changes in expression of genes including BAX and FAS (involved in apoptosis), NADPH dehydrogenase (mitochondria), EGFR (cellular survival) and RAD51 (DNA damage repair) while sodium lactate increased cellular metabolism rather than changing the gene expression. Conclusion: Our results suggest that various tumor microenvironmental factors can differentially influence DNA methylation and hence radiosensitivity and gene expression in A549 cancer cells.

• Tuberculosis and Respiratory Diseases
• /
• v.45 no.2
• /
• pp.290-300
• /
• 1998

Background: CYFRA 21-1 is a tumor marker which measures a fragment of cytokeratin 19 expressed by epithelial cells in bronchus. It is known that cytokeratin 19 is abundant in squamous epithelial cell cancer of the lung. However, if the incidence of elevated serum CYFRA 21-1 level in patients with benign lung diseases or pulmonary tuberculosis with severe parenchymal damage is high the specificity of CYFRA 21-1 could be decreased. The purpose of this study is to investigate the changes of serum CYFRA 21-1 according to the degree of parenchymal damage and the usefulness of CYFRA 21-1 for diagnosing possibly combined lung cancer in patients with pulmonary tuberculosis. Method: We studied the changes of serum CYFRA 21-1 according to the sputum AFB stain, radiologic manifestation and history of treatment in 81 patients with pulmonary tuberculosis, and 20 healthy persons, 25 patients with lung cancer, as a control group. CYFRA 21-1 concentration in serum was quantified by the immunoradiometry assay(Centocor$^{(R)}$). Result: The results were as follow; Serum CYFRA 21-1 level was significantly lower in patients with pulmonary tuberculosis($1.54{\pm}1.19ng/mL$, p<0.01) as compared to patients with lung cancer($12.25{\pm}15.97ng/mL$), and was slightly higher than the level in heathy persons($0.90{\pm}0.49ng/mL$) but there was no significant difference. Serum CYFRA 21-1 level was below the cut-off value of 3.3ng/mL in 95 percent of patients with pulmonary tuberculosis but it was above the cut-off value in 64 percent of patients with lung cancer. Serum CYFRA 21-1 level was significantly higher in the initial treatment group($1.91{\pm}1.55ng/mL$, p<0.05) as compared to the treatment. failure group ($0.92{\pm}0.30ng/mL$). According to the sputum AFB smear, serum CYFRA 21-1 level in patients with negative result was slightly higher than the level in patients with positive result but there was no significant difference. According to the radiologic manifestation, serum CYFRA 21-1 level was significantly higher in patients with infiltrative lesion ($2.15{\pm}1.63ng/mL$, p<0.01) as compared to patients with destructive lesion ($l.04{\pm}0.54ng/mL$). As the size of cavity or destructive lesion was larger, the level was significantly lower(p<0.05). Conclusion: As serum CYFRA 21-1 level was significantly higher in the initial treatment group and patients with infiltrative lesion, it suppose to be closely related with the degree of parenchymal damage of the lung of the pulmonary tuberculosis. However CYFRA 21-1 could be useful method for diagnosing lung cancer even in patients with pulmonary tuberculosis combined with lung cancer because of the fact that it was below the cutoff value of 3.3ng/mL in 95 percent of patients with pulmonary tuberculosis.

• The Journal of Internal Korean Medicine
• /
• v.33 no.4
• /
• pp.405-417
• /
• 2012

Objectives : In the present study, anti-metastatic properties of the methanol extract of L. obtusiloba (MLO) were evaluated. Methods : To determine the effect of MLO on cancer metastasis, we checked matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) activities and expressions in B16F10 melanoma cells. In addition, we performed cell migration assay as well as invasion assay using Matrigel. Finally, we used an in vivo lung metastasis model to confirm the anti-metastatic activity of MLO. Results : 1. MLO showed potent inhibitory effects on MMP-2 and MMP-9 activities and expressions via down-regulation of activation of NF-${\kappa}B$ in B16F10 melanoma cells. 2. Melanoma cell migration and invasion were down-regulated by MLO treatment. 3. Not only in vitro model, but MLO also significantly suppressed lung metastasis in vivo. Conclusions : The present results indicate that MLO has strong inhibitory effect on cancer metastasis. Therefore, L. obtusiloba could be a valuable anti-metastatic agent.

• Tuberculosis and Respiratory Diseases
• /
• v.42 no.6
• /
• pp.846-854
• /
• 1995

Background: Cytokeratin 19 is a subunit of cytokeratin intermediate filament expressed in simple epithelia such as respiratory epithelial cells and their malignant counterparts. An immunoradiometric assay is available to detect a fragment of the cytokeratin, referred to as Cyfra 21-1 in the serum. This study was conducted to evaluate the clinical utility of this new marker in the diagnosis of lung cancer compared with established markers of squamous cell carcinoma antigen (SCC Ag) and carcino-embryonic antigen(CEA). In addition, we compared the diagnostic sensitivity and specificity of Cyfra 21-1 with those of SCC Ag in squamous cell carcinoma of the lung. We also measured the level of Cyfra 21-1 in the different stages of squamous cell carcinoma of the lung. Method: We measured Cyfra 21-1(ELSA-CYFRA 21-1), SCC Ag(ABBOTT SCC RIABEAD) and CEA(ELSA2-CEA) in 79 patients with primary lung cancer and in 78 persons as a comparison group including 32 patients with pulmonary tuberculosis, 23 patients with benign lung disease and 23 cases with healthy individual. Cyfra 21-1 is measured by a solid-phase immunoradiometric assay(CIS Bio International, France) based on the two-site sandwich method. SCC Ag is measured by a radioimmunoassay(Abbott Laboratories, USA). CEA is measured by a immunoradiometric assay(CIS Bio International, France). All data were expressed as the mean$\pm$standard deviation. Results: 1) The mean value of Cyfra 21-1 was $18.38{\pm}3.65\;ng/mL$ in the lung cancer and $1.l6{\pm}0.53\;ng/mL$ in the comparison group(p<0.0001). SCC Ag was $3.53{\pm}6.06\;ng/mL$ in the lung cancer and $1.19{\pm}0.5\;ng/mL$ in the comparison group(p<0.01). CEA was $35.03{\pm}13.9\;ng/mL$ in the lung cancer and $2.89{\pm}1.01\;ng/mL$ in the comparison group(p<0.0001). 2) Cyfra 21-1 level in squamous cell carcinoma($31.52{\pm}40.13\;ng/mL$) was higher than that in adenocarcinoma($2.41{\pm}1.34\;ng/mL$)(p<0.0001) and small cell carcinoma($2.15{\pm}2.05\;ng/mL$)(p=0.007). SCC Ag level in squamous cell carcinoma($5.1{\pm}7.68\;ng/mL$) was higher than that in adenocarcinoma($1.36{\pm}0.69\;ng/mL$)(p=0.009) and small cell carcinoma($1.1{\pm}0.24\;ng/mL$) (p=0.024). 3) The level of Cyfra 21-1 was not correlated with the progression of stage in squamous cell carcinoma of the lung. 4) Using the cut-off value of 3.3ng/mL, the diagnostic sensitivity of Cyfra 21-1 was 83% in squamous cell carcinoma, 22% in adenocarcinoma and 17% in small cell carcinoma. The sensitivity of SCC Ag and CEA were 39% and 20%, respectively in squamous cell carcinoma, 11% and 39% in adenocarcinoma, and 0% and 33% in small cell carcinoma. 5) Comparison of the receiver operating characteristics curves(ROC curve) for Cyfra 21-1, SCC Ag and CEA revealed that Cyfra 21-1 showed highest diagnostic sensitivity among them in the diagnosis of lung cancer. Conclusion: Cyfra 21-1 is thought to be a better tumor marker for the diagnosis of lung cancer than SCC Ag and CEA, especially in squamous cell carcinoma of the lung.

• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.10
• /
• pp.4331-4338
• /
• 2014

$N^1$-(2, 5-dimethoxyphenyl)-$N^8$-hydroxyoctanediamide (N25) is a novel SAHA cap derivative of HDACi, with a patent (No. CN 103159646). This invention is a hydroxamic acid compound with a structural formula of $RNHCO(CH_2)6CONHOH$ (wherein R=2, 5dimethoxyaniline), a pharmaceutically acceptable salt which is soluble. In the present study, we investigated the effects of N25 with regard to drug distribution and molecular docking, and anti-proliferation, apoptosis, cell cycling, and $LD_{50}$. First, we designed a molecular approach for modeling selected SAHA derivatives based on available structural information regarding human HDAC8 in complex with SAHA (PDB code 1T69). N25 was found to be stabilized by direct interaction with the HDAC8. Anti-proliferative activity was observed in human glioma U251, U87, T98G cells and human lung cancer H460, A549, H1299 cells at moderate concentrations ($0.5-30{\mu}M$). Compared with SAHA, N25 displayed an increased antitumor activity in U251 and H460 cells. We further analyzed cell death mechanisms activated by N25 in U251 and H460 cells. N25 significantly increased acetylation of Histone 3 and inhibited HDAC4. On RT-PCR analysis, N25 increased the mRNA levels of p21, however, decreased the levels of p53. These resulted in promotion of apoptosis, inducing G0/G1 arrest in U251 cells and G2/M arrest in H460 cells in a time-dependent and dose-dependent manner. In addition, N25 was able to distribute to brain tissue through the blood-brain barrier of mice ($LD_{50}$: 240.840mg/kg). In conclusion, our findings demonstrate that N25 will provide an invaluable tool to investigate the molecular mechanism with potential chemotherapeutic value in several malignancies, especially human glioma.

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

• Journal of Pharmaceutical Investigation
• /
• v.33 no.2
• /
• pp.105-112
• /
• 2003

Selective COX (cyclooxygenase)-2 inhibitors including celecoxib have been shown to induce apoptosis and cell cycle changes in various tumor cells. New inhibitors are recently being developed as chemomodulating agents. We evaluated celecoxib and screened 150 synthetic compounds for anti-proliferative activities in vitro. Effects of celecoxib on COX activity, cell growth, cell cycle distribution, and apoptosis induction were determined in A549 COX-2 overexpressing human non-small cell lung cancer (NSCLC) cells. The COX inhibition of celecoxib increased with concentration up to 82% at $1\;{\mu}M$ after 24 hr exposure. Forty ${\mu}M$ and $50\;{\mu}M$ of ce1ecoxib induced $G_1$ arrest, and TUNEL-positive apoptotic cells, respectively. Among 150 compounds, several compounds were selected for having greater COX-2 inhibitory activity and higher selectivity than celecoxib with growth inhibitory activity. Celecoxib showed concentration-dependent COX inhibitory activity, and ability to induce cell cycle arrest and apoptosis in human NSCLC cells in vitro. Among synthetic analogues screened, several compounds showed promising in vitro activity as COX-2 inhibitory anticancer agents, which warrant further evaluation in vitro and in vivo.

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.18
• /
• pp.8203-8210
• /
• 2016

Adenocarcinomas (AC) are the most frequently encountered carcinomas. It may be quite challenging to detect the primary origin when those carcinomas metastasize and the first finding is a metastatic tumor. This study evaluated the role of sex hormone binding globulin (SHBG) positivity in tumor cells in the subclassification and detection of the original organ of adenocarcinomas. Between 1994 and 2008, 64 sections of normal tissue belonging to ten organs, and 116 cases diagnosed as adenoid cystic carcinoma and mucoepidermoid carcinoma of the salivary gland, lung adenocarcinoma, invasive ductal carcinoma of the breast, adenocarcinoma of stomach, colon, gallbladder, pancreas and prostate, endometrial adenocarcinoma and serous adenocarcinoma and mucinous adenocarcinoma of the ovary, were sent to the laboratory at the Department of Pathology at the Yuzuncu Yil University School of Medicine, where they were stained immunohistochemically, using antibodies against SHBG. The SHBG immunoreactivity in both the tumor cells and normal cells, together with the type, diffuseness and intensity of the staining were then evaluated. In the differential diagnosis of the adenocarcinomas of the organs, including the glandular structures, impressively valuable results are encountered in the tumor cells, whether the SHBG immunopositivity is evaluated alone or together with other IHC markers. Further extensive research with a larger number of cases, including instances of cholangiocarcinoma and cervix uteri AC [which we could not include in the study for technical reasons] should be performed, in order to appropriately evaluate the role of SHBG in the differential diagnosis of AC.

• The Journal of Internal Korean Medicine
• /
• v.37 no.1
• /
• pp.16-25
• /
• 2016

Objectives: Gilgyung-tang (GGT) has been used as one of the main multi-herb formulas to treat “Peo-ong” (lung abscess). In this study, we investigated the inhibitory effects of water extracts of GGT on cell migration and invasion, two critical cellular processes that are often deregulated during metastasis, in human bladder cancer 5637 cells.Methods: Effects on cell viability were quantified using an MTT assay. To analyze the anti-metastatic effects, we conducted a wound healing migration assay, an in vitro invasiveness assay, and a measurement of the transepithelial electrical resistance (TER). The expression of protein and mRNA were measured by Western blotting and real-time polymerase chain reaction (RT-PCR), respectively.Results: GGT markedly inhibited the cell motility and invasiveness of 5637 cells within the concentration range that was not cytotoxic. The inhibitory effects of GGT on cell invasiveness were associated with tightening of the tight junctions (TJs), which was demonstrated by an increase in the TER. The RT-PCR and Western blotting results indicated that GGT decreased the levels of claudin proteins. GGT also inhibited the activity and expression of matrix metalloproteinase (MMP)-2 and -9 and simultaneously increased the levels of tissue inhibitor of metalloproteinase-1 and -2.Conclusions: Our findings suggest that GGT reduces both the migration and the invasion of 5637 cells by modulating the activity of TJs and MMPs.