• Journal of Medicine and Life Science
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• v.15 no.2
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• pp.46-50
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• 2018

Cancer, a leading mortality disease following cardiovascular disease worldwide, has high incidence as one out of every four adults in Korea. It was known to be caused by several reasons including somatic mutation, activation of oncogene and chromosome aneuploidy. Cancer cells show a faster growth rate and have metastatic and heterogeneous cell populations compared to normal cells. Cancer stem cells, the most invested field in cancer biology, is a theory to explain heterogeneous cell populations of cancer cells among several characteristics of cancer cells, which is providing the theoretical background for incidence of cancer and treatment failure by drug resistance. Cancer stem cells initially explain heterogeneous cell populations of cancer cells based on the same markers of normal stem cells in cancer, in which only cancer stem cells showed heterogeneity of cancer cells and tumor initiating ability of leukemia. Based on these results, cancer stem cells were reported in various solid cancers such as breast cancer, liver cancer, and lung cancer. Breast cancer stem cells were first reported in solid cancer which had tumor initiating ability and further identified as anti-cancer drug resistance. There were several identification methods in breast cancer stem cells such as specific surface markers and culture methods. The discovery of cancer stem cells not only explains heterogeneity of cancer cells, but it also provides theoretical background for targeting cancer stem cells to complete elimination of cancer cells. Many institutes have been developing new anticancer drugs targeting cancer stem cells, but there have not been noticeable results yet. Many researchers also reported a necessity for improvement of current concepts and methods of research on cancer stem cells. Herein, we discuss the limitations and the perspectives of breast cancer stem cells based on the current concept and history.

• Journal of Nutrition and Health
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• v.51 no.3
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• pp.208-214
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• 2018

Purpose: Platycodon grandiflorum (a domestic diploid variety, DV-PG) has been used as a food and component of various traditional oriental medicines. Although DV-PG is known to have an anti-allergic effect, little is known about the beneficial health effects of the tetraploid 'Etteum' variety in the Platycodon grandiflorum (TV-PG), which is a recently developed variety. In this study, we investigated the effect of TV-PG on the rat basophilic leukemia mast cell (RBL-2H3)-mediated allergic response. Methods: To examine the effects of TV-PG on the allergic response, RBL-2H3 cells were sensitized with dinitropheny (DNP)-immunoglobin E, treated with various concentrations of TV-PG, and challenged with DNP-human serum albumin. We estimated cell granulation by measuring the release of ${\beta}$-hexosaminidase and production of inflammatory mediators by ELISA. Results: TV-PG had no effect on the proliferation or cytotoxicity of RBL-2H3 cells within the concentration range of 0 to $200{\mu}g/mL$. TV-PG inhibited degranulation of RBL-2H3 cells by antigen stimulation in a dose-dependent manner. TV-PG also suppressed the production of inflammatory cytokines and mediators such as interleukin-4, tumor necrosis $factor-{\alpha}$, prostagladin E2, and leukotriene B4 in RBL-2H3 cells by antigen stimulation. Conclusion: These results indicate that TV-PG exhibits anti-allergic activity via inhibition of degranulation as well as suppression of inflammatory mediators and cytokine release. These findings suggest that TV-PG may have potential as a preventive and therapeutic agent for the treatment of various allergic diseases.

• Korean Journal of Clinical Pharmacy
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• v.29 no.2
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• pp.79-88
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• 2019

Backgrounds: Inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn's disease (CD) increased prevalence and economic burden. Objectives: This study aimed to investigate drug use pattern in IBD patients in a real world. Methods: National Health Insurance claim data from 2010 to 2014 were used in this population-based study. All IBD patients diagnosed during study period were enrolled. IBD medications included 5-aminosalicylic acid (ASA), glucocorticoid, immunomodulator and anti-tumor necrosis factor-${\alpha}$ agent(anti TNF-${\alpha}$). Growth rate of IBD prevalence, prescribed drug classes, duration of drug therapy and medication cost were analyzed. Number and percentage of patients for categorical variables, and mean and median for continuous variables were presented. Results: Total numbers of patients were 131,158 and 57,286 during 5 years, and their annual growth rate were 3.2 and 5.7% for UC and CD. UC and CD were prevalent in the 40-50 (41.2%) and 20-30 age groups (36.0%). About 60% of IBD patients was prescribed any of medications. 5-ASA was the most frequently prescribed, followed by corticosteroid and immunomodulator. Anti TNF-${\alpha}$ use was the lowest, but 5 times higher than UC in CD. Combination therapies with different class of drugs were in 29% for UC and 62% for CD. Mean prescription days per patient per year were 306 and 378, and the median medication cost per patient per year was KRW 420,000 (USD 383) and KRW 830,000 (USD755), for UC and CD, respectively. Conclusions: Increasing prevalence of IBD requires further studies to contribute to achieve better clinical outcomes of drug therapy.

• Biomolecules & Therapeutics
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• v.32 no.1
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• pp.115-122
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• 2024

Heat shock protein (HSP) 90 is expressed in most living organisms, and several client proteins of HSP90 are necessary for cancer cell survival and growth. Previously, we found that HSP90 was cleaved by histone deacetylase (HDAC) inhibitors and proteasome inhibitors, and the cleavage of HSP90 contributes to their cytotoxicity in K562 leukemia cells. In this study, we first established mouse xenograft models with K562 cells expressing the wild-type or cleavage-resistant mutant HSP90β and found that the suppression of tumor growth by the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was interrupted by the mutation inhibiting the HSP90 cleavage in vivo. Next, we investigated the possible function of thioredoxin interacting protein (TXNIP) in the HSP90 cleavage induced by SAHA. TXNIP is a negative regulator for thioredoxin, an antioxidant protein. SAHA transcriptionally induced the expression of TXNIP in K562 cells. HSP90 cleavage was induced by SAHA also in the thymocytes of normal mice and suppressed by an anti-oxidant and pan-caspase inhibitor. When the thymocytes from the TXNIP knockout mice and their wild-type littermate control mice were treated with SAHA, the HSP90 cleavage was detected in the thymocytes of the littermate controls but suppressed in those of the TXNIP knockout mice suggesting the requirement of TXNIP for HSP90 cleavage. We additionally found that HSP90 cleavage was induced by actinomycin D, β-mercaptoethanol, and p38 MAPK inhibitor PD169316 suggesting its prevalence. Taken together, we suggest that HSP90 cleavage occurs also in vivo and contributes to the anti-cancer activity of various drugs in a TXNIP-dependent manner.

• Biomolecules & Therapeutics
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• v.32 no.3
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• pp.267-280
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• 2024

Apoptosis, programmed cell death pathway, is a vital physiological mechanism that ensures cellular homeostasis and overall cellular well-being. In the context of cancer, where evasion of apoptosis is a hallmark, the overexpression of anti-apoptotic proteins like Bcl2, Bcl-xL and Mcl-1 has been documented. Consequently, these proteins have emerged as promising targets for therapeutic interventions. The BCL-2 protein family is central to apoptosis and plays a significant importance in determining cellular fate serving as a critical determinant in this biological process. This review offers a comprehensive exploration of the BCL-2 protein family, emphasizing its dual nature. Specifically, certain members of this family promote cell survival (known as anti-apoptotic proteins), while others are involved in facilitating cell death (referred to as pro-apoptotic and BH3-only proteins). The potential of directly targeting these proteins is examined, particularly due to their involvement in conferring resistance to traditional cancer therapies. The effectiveness of such targeting strategies is also discussed, considering the tumor's propensity for anti-apoptotic pathways. Furthermore, the review highlights emerging research on combination therapies, where BCL-2 inhibitors are used synergistically with other treatments to enhance therapeutic outcomes. By understanding and manipulating the BCL-2 family and its associated pathways, we open doors to innovative and more effective cancer treatments, offering hope for resistant and aggressive cases.

• Journal of Microbiology and Biotechnology
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• v.32 no.10
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• pp.1262-1274
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• 2022

Cholangiocarcinoma (CCA) is a complex and refractor type of cancer with global prevalence. Several barriers remain in CCA diagnosis, treatment, and prognosis. Therefore, exploring more biomarkers and therapeutic drugs for CCA management is necessary. CCA gene expression data was downloaded from the TCGA and GEO databases. KEGG enrichment, GO analysis, and protein-protein interaction network were used for hub gene identification. miRNA were predicted using Targetscan and validated according to several GEO databases. The relative RNA and miRNA expression levels and prognostic information were obtained from the GEPIA. The candidate drug was screened using pharmacophore-based virtual screening and validated by molecular modeling and through several in vitro studies. 301 differentially expressed genes (DEGs) were screened out. Complement and coagulation cascades-related genes (including AHSG, F2, TTR, and KNG1), and cell cycle-related genes (including CDK1, CCNB1, and KIAA0101) were considered as the hub genes in CCA progression. AHSG, F2, TTR, and KNG1 were found to be significantly decreased and the eight predicted miRNA targeting AHSG, F2, and TTR were increased in CCA patients. CDK1, CCNB1, and KIAA0101 were found to be significantly abundant in CCA patients. In addition, Molport-003-703-800, which is a compound that is derived from pharmacophores-based virtual screening, could directly bind to CDK1 and exhibited anti-tumor activity in cholangiocarcinoma cells. AHSG, F2, TTR, and KNG1 could be novel biomarkers for CCA. Molport-003-703-800 targets CDK1 and work as potential cell cycle inhibitors, thereby having potential for consideration for new chemotherapeutics for CCA.

• The Korean Journal of Pain
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• v.28 no.4
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• pp.236-243
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• 2015

Background: Chemotherapy-induced peripheral neuropathy is a major side effect of anti-cancer drugs, and our knowledge of its mechanisms is lacking. Several models for chemotherapy-induced neuropathy have been introduced. However, the outcomes of these models differ significantly among laboratories. Our object was to create a model of chemotherapy-induced neuropathy in rats with cancer. Methods: Female Sprague-Dawley rats were used. Mammary rat metastasis tumor (MRMT-1) cells were implanted subcutaneously in rats. Chemotherapy-induced peripheral neuropathy was induced by injection of cisplatin once a day for four days. The responses to mechanical and thermal stimuli were examined using von Frey filaments, acetone, and radiant heat. Results: Cisplatin (2 mg/kg/day) produced mechanical allodynia, while it did not induce cold allodynia or thermal hyperalgesia. This dose of cisplatin could work successfully against cancer. Body weight loss was not observed in cisplatin-treated rats, nor were other abnormal behaviors noted in the same rats. Conclusions: Repeated injection of intraperitoneal cisplatin induced peripheral neuropathic pain in rats. Thus, this type of rat model has broad applicability in studies related to searching for the mechanism of cisplatin-induced mechanical allodynia and agents for the treatment of neuropathic pain.

• Korean Journal of Veterinary Research
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• v.43 no.4
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• pp.607-613
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• 2003

Dendritic cells (DCs) play an essential role in a variety of immune reactions involving $CD4^+$ T cells and have been used to enhance tumor-specific immune responses. Immunosuppression in patients with cancer includes the downregulation of function and number of DCs. Although DCs have been studied, the apoptosis of Des induced by anticancer drugs for chemotherapy remains largely uncharacterized. This study demonstrated that GM-CSF protects DCs from 5-fluorouracil (5-FU) or mitomycin C-induced apoptosis. After 6 - 10 days culture, DCs were characterized by specific surface marker, CD11c and MHC class II. MTT assay revealed that GM-CSF significantly enhanced the viability of DCs treated with 5-FU or mitomycin C. The percentage of dead cells of DCs was determined by cell size using FACScan and GM-CSF was clearly effective. However, GM-CSF did not increase the expression of MHC class II on viable DCs gated, suggesting that GM-CSF may differentially regulate critical factors involved in the function of DCs. For the quantitative analysis of apoptosis, annexin V-FITC staining was performed. 5-FU induced the apoptosis of DCs and GM-CSF significantly protects DCs from 5-FU-induced apoptosis. Taken together, the results in this study that GM-CSF has an anti-apoptosis effect on DCs may provide patients with cancer with clinical benefits to overcome the immunosuppression induced by the decrease of number and functional insufficiency of DCs.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6343-6347
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• 2014

Multi-target drug design, in which drugs are designed as single molecules to simultaneously modulate multiple physiological targets, is an important strategy in the field of drug discovery. QT-011, a tamibarotene-furoxan derivative, was here prepared and proposed to exert synergistic effects on antileukemia by releasing nitric oxide and tamibarotene. Compared with tamibarotene itself, QT-011 displayed stronger antiproliferative effects on U937 and HL-60 cells and was more effective evaluated in a nude mice U937 xenograft model in vivo. In addition, QT-011 could release nitric oxide which might contribute to the antiproliferative activity. Autodocking assays showed that QT-011 fits well with the hydrophobic pocket of retinoic acid receptors. Taken together, these results suggest that QT-011 might be a highly effective derivative of tamibarotene and a potential candidate compound as antileukemia agent.

• Natural Product Sciences
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• v.16 no.3
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• pp.185-191
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• 2010

Mast cell-mediated allergic disease is involved in many diseases such as anaphylaxis, asthma and atopic dermatitis. The discovery of drugs for the treatment of allergic disease is an important subject in human health. In the present study, the effect of water extract of Gleditsiae Spina (WGS) (Leguminosae), on compound 48/80-induced systemic allergic reaction, anti-DNP IgE antibody-induced local allergic reaction, and histamine release from human mast cell line (HMC-1) cells were studied. In addition, the effect of WGS on phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187 (A23187)-induced gene expression and secretion of pro-inflammatory cytokines were investigated using HMC-1 cells. WGS was anally administered to mice for high and fast absorption. WGS inhibited compound 48/80-induced systemic allergic reaction. WGS dose-dependently decreased the IgE-mediated passive cutaneous anaphylaxis. WGS reduced histamine release from HMC-1 cells. In addition, WGS decreased the gene expression and secretion of pro-inflammatory cytokines in PMA plus A23187-stimulated HMC-1 cells. These findings provide evidence that WGS could be a candidate as an antiallergic agent.