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Identification of a New Selective Chemical Inhibitor of Mutant Isocitrate Dehydrogenase-1.

Hyo Joon KIM ; Bu Young CHOI ; Young Sam KEUM

Journal of Cancer Prevention.2015;20(1):78-83. doi:10.15430/JCP.2015.20.1.78

BACKGROUND: Recent genome-wide sequencing studies have identified unexpected genetic alterations in cancer. In particular, missense mutations in isocitrate dehydrogenase-1 (IDH1) at arginine 132, mostly substituted into histidine (IDH1-R132H) were observed to frequently occur in glioma patients. METHODS: We have purified recombinant IDH1 and IDH1-R132H proteins and monitored their catalytic activities. In parallel experiments, we have attempted to find new selective IDH1-R132H chemical inhibitor(s) from a fragment-based chemical library. RESULTS: We have found that IDH1, but not IDH1-R132H, can catalyze the conversion of isocitrate into alpha-ketoglutarate (alpha-KG). In addition, we have observed that IDH1-R132H was more efficient than IDH1 in converting alpha-KG into (R)-2-hydroxyglutarate (R-2HG). Moreover, we have identified a new hit molecule, e.g., 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one as a new selective IDH1-R132H inhibitor. CONCLUSIONS: We have observed an underlying biochemical mechanism explaining how a heterozygous IDH1 mutation contributes to the generation of R-2HG and increases cellular histone H3 trimethylation levels. We have also identified a novel selective IDH1-R132H chemical hit molecule, e.g., 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one, which could be used for a future lead development against IDH1-R132H.
Arginine ; Glioma ; Histidine ; Histones ; Humans ; Mutation, Missense

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Clinical Implication of p16, Ki-67, and Proliferating Cell Nuclear Antigen Expression in Cervical Neoplasia: Improvement of Diagnostic Accuracy for High-grade Squamous Intraepithelial Lesion and Prediction of Resection Margin Involvement on Conization Spe.

Tae Hun KIM ; Jee Hye HAN ; Eun SHIN ; Jae Hong NOH ; Hee Seung KIM ; Yong Sang SONG

Journal of Cancer Prevention.2015;20(1):70-77. doi:10.15430/JCP.2015.20.1.70

BACKGROUND: Cervical intraepithelial neoplasia (CIN) grading is subjective and affected by substantial rates of discordance among pathologists. Although the use of p16INK4a (p16) staining has been proven to improve diagnostic accuracy for high-grade squamous intraepithelial lesion (HSIL), the clinical evidence for use of Ki-67 and proliferating cell nuclear antigen (PCNA) is insufficient to make an independent recommendation for use, alone or in combination. The primary objective was to evaluate clinical utility of Ki-67 and PCNA in combination with p16 in diagnosing HSIL. Also, we assessed the correlation between expressions of three biomarkers and resection margin status of conization specimen. METHODS: The expressions of p16, Ki-67, and PCNA were evaluated by immunohistochemical methods in 149 cervical tissues encompassing 17 negative lesion, 31 CIN 1, 25 CIN 2, 41 CIN 3, and 35 invasive squamous cell carcinoma. The immunohistochemical staining results were classified into four grades: 0, 1+, 2+ and 3+. RESULTS: The expression of three biomarkers was positively associated with CIN grade. Ki-67 immunostaining did not increase the accuracy of HSIL diagnosis when combined with p16 immunostaining compared with p16 immunostaining alone. In contrast, combining the staining results for p16 and PCNA (p16 = 3+ and PCNA > or =2+) increased its specificity (66.7% vs. 75.0%, P = 0.031) without decrease of its sensitivity (98.7% vs. 98.7%) for diagnosis of CIN 3 and more sever lesion. Subgroup analysis for conization specimen with CIN 2 and CIN 3 showed that positive Ki-67 immunostaining was an independent risk factor for predicting resection margin positivity (odds ratio = 6.52, 95% confidence interval 1.07-39.64). CONCLUSIONS: We found that the combined use of p16 and PCNA immunostaining enhanced diagnostic accuracy for HSIL. Positive Ki-67 immunostaining was associated with incomplete excision.
Biomarkers ; Carcinoma, Squamous Cell ; Cervical Intraepithelial Neoplasia ; Conization* ; Diagnosis ; Proliferating Cell Nuclear Antigen* ; Risk Factors ; Sensitivity and Specificity

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A Controlled, Randomized, Double-blind Trial to Evaluate the Effect of Vegetables and Whole Grain Powder That Is Rich in Dietary Fibers on Bowel Functions and Defecation in Constipated Young Adults.

Hye Im WOO ; Shin Hye KWAK ; Yeojin LEE ; Ji Hee CHOI ; Young Mi CHO ; Ae Son OM

Journal of Cancer Prevention.2015;20(1):64-69. doi:10.15430/JCP.2015.20.1.64

BACKGROUND: This study evaluated the effect of vege-powder (VP), mainly consisted of chicory, broccoli, and whole grains, on bowel habit improvement and constipation alleviation. METHODS: Using the Roman standard II, 96 male and female subjects in their twenties with constipation symptoms were divided into a control group or VP group. Subjects in a control group were supplied with rice flakes-powder (RFP) and subjects in the VP group were provided with 30 g of VP twice daily for 4 weeks. Constipation relief effectiveness was surveyed on 5-point Likert scales depending on stool hardness, amount of stool, sensation of incomplete evacuation, and straining to defecate at day 0, 14, and 28 of RFP or VP intake. RESULTS: Repeated measures analysis of variance analysis revealed that VP intake caused significant temporal changes in stool hardness, amount, sensation of incomplete evacuation, and straining to defecate. In addition, significant differences between control and VP groups were found in stool hardness, amount, sensation of incomplete evacuation, and straining to defecate at day 14 and 28 of experimental diet consumption. VP supplement for 2 weeks significantly increased the evacuation frequency (1.04 +/- 0.71), compared to control group (0.41 +/- 0.64) and this increase was maintained at 4 week of diet supplements. CONCLUSIONS: This result showed that constipated subjects who consumed VP, mainly consisting of chicory, broccoli, and whole grains, improved constipation symptoms at 2 and 4 weeks of consumption compared to those of control group who were provided with RFP.
Brassica ; Edible Grain* ; Chicory ; Constipation ; Defecation* ; Diet ; Dietary Fiber* ; Female ; Hardness ; Humans ; Male ; Sensation ; Vegetables* ; Weights and Measures ; Young Adult*

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Inhibition of Ubiquitin-specific Peptidase 8 Suppresses Growth of Gefitinib-resistant Non-small Cell Lung Cancer Cells by Inducing Apoptosis.

Chul Ho JEONG

Journal of Cancer Prevention.2015;20(1):57-63. doi:10.15430/JCP.2015.20.1.57

BACKGROUND: Therapeutic approach by treatment with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib or erlotinib to non-small cell lung cancer (NSCLC) patients has been limited due to emergence of acquired drug resistance. Our study was aimed to investigate whether the inhibition of ubiquitin-specific peptidase 8 (USP8) could be an alternative strategy capable of overcoming acquired resistance to EGFR-TKIs for treatment of NSCLCs. METHODS: The anticancer effect of USP8 inhibitor was determined by testing anchorage-dependent or independent growth of gefitinib-sensitive or resistant NSCLCs. The immunoprecipitation and western blotting were conducted to check molecular interaction and signaling pathway followed by USP8 inhibition. RESULTS: Inhibition of USP8 induced overall degradation of oncogenic receptor tyrosine kinases including EGFR and Met, leading to a suppression of anchorage-dependent or independent cell growth of gefitinib-sensitive or resistant NSCLCs. Also, treatment with the USP8 inhibitor markedly induced apoptosis in HCC827GR cells. Notably, treatment with the USP8 inhibitor was more effective in suppressing cell growth and inducing apoptosis in gefitinib-resistant HCC827GR cells than that of gefitinib-sensitive HCC827 cells. CONCLUSIONS: Inhibition of USP8 could be an effective strategy for overcoming gefitinib resistance in NSCLCs.
Apoptosis* ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung* ; Drug Resistance ; Epidermal Growth Factor ; Erlotinib Hydrochloride ; Humans ; Immunoprecipitation ; Phosphotransferases ; Tyrosine

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Anthocyanins From the Fruit of Vitis coignetiae Pulliat Potentiate the Cisplatin Activity by Inhibiting PI3K/Akt Signaling Pathways in Human Gastric Cancer Cells.

Jing Nan LU ; Won Sup LEE ; Arulkumar NAGAPPAN ; Seong Hwan CHANG ; Yung Hyun CHOI ; Hye Jung KIM ; Gon Sup KIM ; Chung Ho RYU ; Sung Chul SHIN ; Jin Myung JUNG ; Soon Chan HONG

Journal of Cancer Prevention.2015;20(1):50-56. doi:10.15430/JCP.2015.20.1.50

BACKGROUND: Cisplatin (cis-diaminedichloroplatinum, CDDP) is a widely used chemotherapeutic agent for the treatment of many cancers. However, initial resistance to CDDP is a serious problem in treating these cancers. Vitis coignetiae Pulliat (Meoru in Korea) have shown anti-nuclear factor kappa B and anti-epidermal growth factor receptor activities in cancer cells. METHODS: In this study, in order to seeking an approach to increase the anti-cancer effects of CDDP with natural products. Here, we investigated anthocyanins isolated from Vitis coignetiae Pulliat (anthocyanidins isolated from meoru, AIMs) can enhance anti-cancer effects of cisplatin (CDDP) in stomach cancer cells. The cell viability of SNU-1 and SNU-16 cells after treated with AIMs and CDDP were analyzed by MTT assay. The expressions of Akt and X-linked inhibitor of apoptosis protein (XIAP) proteins were examined by western blot in AIMs- and CDDP-treated cells. RESULTS: We found that AIMs enhanced anticancer effects of CDDP, which activity was additive but not synergistic. AIMs suppressed Akt activity of the cancer cells activated by CDDP. AIMs also suppressed in XIAP an anti-apoptotic protein. CONCLUSIONS: This study suggests that the anthocyanins isolated from fruits of Vitis coignetiae Pulliat enhanced anti-cancer effects of CDDP by inhibiting Akt activity activated by CDDP.
Anthocyanins* ; Biological Products ; Blotting, Western ; Cell Survival ; Cisplatin* ; Fruit* ; Humans* ; Stomach Neoplasms* ; Vitis* ; X-Linked Inhibitor of Apoptosis Protein

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Analysis of Gastric Body Microbiota by Pyrosequencing: Possible Role of Bacteria Other Than Helicobacter pylori in the Gastric Carcinogenesis.

Sung Hwa SOHN ; Nayoung KIM ; Hyun Jin JO ; Jaeyeon KIM ; Ji Hyun PARK ; Ryoung Hee NAM ; Yeong Jae SEOK ; Yeon Ran KIM ; Dong Ho LEE

Journal of Cancer Prevention.2017;22(2):115-125. doi:10.15430/JCP.2017.22.2.115

BACKGROUND: Gastric microbiota along with Helicobacter pylori (HP) plays a key role in gastric disease. The aim of our study is to investigate the difference of human gastric microbiota between antrum and body according to disease (control vs. gastric cancer) and HP status. METHODS: Each antrum and body biopsy was collected from 12 subjects at Seoul National University Bundang Hospital. Gastric microbiota was analyzed by bar-coded 454 pyrosequencing of the 16S rRNA gene. Twelve subjects consisted of HP-negative control (n = 2), HP-negative cancer (n = 2), HP-positive control (n = 3), and HP-positive cancer (n = 5). The analysis was focused on non-HP urease-producing bacteria (UB) and non-HP nitrosating or nitroreducing bacteria (NB) between antrum and body. RESULTS: Gastric body samples showed higher diversity compared to gastric antrum mucosa samples but there was no significant difference. The mean of operational taxonomic units was higher in HP(−) cancer than HP(+) cancer (antrum, 273.5 vs. 228.2, P = 0.439; body, 585.5 vs. 183.2, P = 0.053). The number of non-HP UB and non-HP NB was higher in HP(−) cancer groups than the others. These differences were more pronounced in the body (P = 0.051 and P = 0.081, respectively). Analysis of overlap of non-HP UB and non-HP NB revealed the higher composition of Streptococcus pseudopneumoniae, S. parasanguinis, and S. oralis in HP(−) cancer groups than the others, only in the body (P = 0.030) but not in the antrum (P = 0.123). CONCLUSIONS: Higher diversity and higher composition of S. pseudopneumoniae, S. parasanguinis, and S. oralis in HP(−) cancer group than the other groups in the body suggest that analysis of microbiota from body mucosa could be beneficial to identify a role of non-HP bacteria in the gastric carcinogenesis.
Bacteria* ; Biopsy ; Carcinogenesis* ; Genes, rRNA ; Helicobacter pylori* ; Helicobacter* ; Humans ; Microbiota* ; Mucous Membrane ; Pyloric Antrum ; Seoul ; Stomach Diseases ; Streptococcus

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Comparisons of Gut Microbiota Among Healthy Control, Patients With Conventional Adenoma, Sessile Serrated Adenoma, and Colorectal Cancer.

Hyuk YOON ; Nayoung KIM ; Ji Hyun PARK ; Yong Sung KIM ; Jongchan LEE ; Hyoung Woo KIM ; Yoon Jin CHOI ; Cheol Min SHIN ; Young Soo PARK ; Dong Ho LEE ; Hyun Chae JUNG

Journal of Cancer Prevention.2017;22(2):108-114. doi:10.15430/JCP.2017.22.2.108

BACKGROUND: Studies on gut microbiota regarding colorectal carcinogenesis, including sessile serrated adenoma (SSA), have been scarce. The aim of this study is to investigate the role of mucosa-associated gut microbiota in the colorectal carcinogenesis. METHODS: We collected biopsy samples of normal rectal mucosa during colonoscopy from healthy control and patients with conventional adenoma, SSA, and colorectal cancer (CRC), respectively (n = 6). Pyrosequencing for 16S rRNA gene of bacteria was performed to compare gut microbiota. RESULTS: The most abundant phylum in total samples was Proteobacteria (55.6%), followed by Firmicutes (27.4%) and Bacteroidetes (11.6%). There was no significant difference in relative abundance of the phylum level among the four groups. Fusobacterium nucleatum, known to be frequently detected during colorectal carcinogenesis, was found in only one sample of patient with SSA. The rarefaction curves showed that the diversity of mucosal communities of patients with CRC is the lowest among the four groups and the diversity of mucosal communities of patients with SSA is higher than that of healthy control. Among the four groups, Shannon's and Simpson's index for diversity was the lowest and the highest in the patients with CRC, respectively; it did not reach statistical significance. The proportion of genus Pseudomonas was very high in the samples of patients with stage II–IV CRC compared with those with stage I CRC (59.3% vs. 0.3%, P = 0.064). CONCLUSIONS: Our study suggests no significant role of mucosa-associated gut microbiota in the colorectal carcinogenesis. Further study for many samples or using fecal material could be helpful.
Adenoma* ; Bacteria ; Bacteroidetes ; Biopsy ; Carcinogenesis ; Colonic Neoplasms ; Colonoscopy ; Colorectal Neoplasms* ; Firmicutes ; Fusobacterium nucleatum ; Gastrointestinal Microbiome* ; Genes, rRNA ; Humans ; Microbiota ; Mucous Membrane ; Proteobacteria ; Pseudomonas

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Prevalence, Age Distribution, and Risk Factors of Visual Inspection With Acetic Acid-Positive From 2007 to 2011 in Jakarta.

Laila NURANNA ; Nyoman Bagus DONNY ; Gatot PURWOTO ; Hariyono WINARTO ; Tofan Widya UTAMI ; Tricia Dewi ANGGRAENI ; Alexander A W PETERS

Journal of Cancer Prevention.2017;22(2):103-107. doi:10.15430/JCP.2017.22.2.103

BACKGROUND: Cervical cancer is still the second most frequent cancer among Indonesian women, thus screening program is still critically important to prevent it. Visual inspection with acetic acid (VIA) was introduced as a method which is most suitable with Indonesia's condition compared with the other screening methods. The Female Cancer Program from Jakarta Regional collaborated with Leiden University in 2007 to 2011 has done cervical cancer screening using VIA method, involving 25,406 women spreading across several primary health centers in Jakarta. By using these data, we found out the prevalence, age distribution, and risk factor of VIA positive in Jakarta as a basis to predict the budget and logistics for the next cervical cancer screening and to do an advocating to the Jakarta's government. METHODS: A secondary data analysis was conducted from several areas in Jakarta from 2007 to 2011. VIA test was used as the screening method, and performed by doctors and midwives with technical supervision by gynecologists. RESULTS: From 25,406 women, there were 1,192 cases (4.7%) of VIA test positive. The risk factors that can significantly influence the result of VIA positive were number of marriage, parity, smoking habits, and the use of hormonal contraception with OR 1.51, 1.85, 1.95, and 0.68, respectively. CONCLUSIONS: Prevalence of VIA test-positive is 4.7% in Jakarta population. The findings of precancerous lesions and cervical cancers are not only between thirty and fifty years old, but also below the thirty years old and after fifty years old. We suggest that VIA test should be performed to all reproductive age and elder women who are not screened yet.
Acetic Acid ; Age Distribution* ; Budgets ; Contraception ; Female ; Humans ; Marriage ; Mass Screening ; Methods ; Midwifery ; Organization and Administration ; Parity ; Prevalence* ; Risk Factors* ; Smoke ; Smoking ; Statistics as Topic ; Uterine Cervical Neoplasms

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Evaluation of the Expression of the Inhibitor of Apoptosis Protein Family and Human Telomerase Reverse Transcriptase in Patients With Advanced Colorectal Adenoma.

Joon Young CHOI ; Hyuk YOON ; Gyeongjae NA ; Yoon Jin CHOI ; Cheol Min SHIN ; Young Soo PARK ; Nayoung KIM ; Dong Ho LEE

Journal of Cancer Prevention.2017;22(2):98-102. doi:10.15430/JCP.2017.22.2.98

BACKGROUND: It has been reported that the expression of the inhibitor of apoptosis protein (IAP) family increases in patients with colon cancer. We evaluated the expression of the IAP family and human telomerase reverse transcriptase (hTERT) in normal colon mucosa from patients with advanced colorectal adenoma and investigated their features according to characteristics of advanced colorectal adenoma. METHODS: While resections of polyps were performed in patients (n = 80) diagnosed with advanced colorectal adenoma or carcinoma in situ, additional normal tissues were obtained from the sigmoid colon. In healthy patients (n = 16), blind biopsies were performed on the sigmoid colon. The expression of the IAP family, including survivin, XIAP, cIAP1, and cIAP2, and hTERT, were analyzed by real-time PCR in both groups. RESULTS: A total of 80 advanced colorectal adenoma patients (71.3% male, mean age of 60.4 years) and 16 control patients were enrolled in this study. The mean ranking of cIAP2 was higher in the control group (68.88 vs. 44.43, P = 0.001). The expression levels of hTERT, survivin, XIAP, and cIAP from both groups showed no differences. The expression of survivin, XIAP, cIAP1, cIAP2, and hTERT depending on certain factors of advanced adenoma, including the number (two or fewer vs. three or more), size (smaller than 1 cm vs. larger than 1 cm), grade of dysplasia (low grade adenoma vs. high grade adenoma), pathology (tubular adenoma vs. villous adenoma), and presence of endometrial intraepithelial neoplasms, showed no significant correlations in the Mann-Whitney U-test. CONCLUSIONS: The expression of the IAP family and hTERT, except cIAP2, in the normal mucosa of patients with advanced colorectal adenoma were not different from those of the control group. There were no differences in the IAP family and hTERT according to the characteristics of advanced adenoma.
Adenoma* ; Biopsy ; Carcinoma in Situ ; Colon ; Colon, Sigmoid ; Colonic Neoplasms ; Humans ; Humans* ; Inhibitor of Apoptosis Proteins* ; Male ; Mucous Membrane ; Pathology ; Polyps ; Real-Time Polymerase Chain Reaction ; Telomerase*

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Antimutagenic and Antioxidant Activities of Thai Rice Brans.

Orapin INSUAN ; Arpamas CHARIYAKORNKUL ; Yuwada RUNGROTE ; Rawiwan WONGPOOMCHAI

Journal of Cancer Prevention.2017;22(2):89-97. doi:10.15430/JCP.2017.22.2.89

BACKGROUND: Rice bran is the outer layer of the rice grain, and contains high amounts of bioactive phytochemicals. Here, we investigated and compared chemopreventive properties of purple and white rice bran extracts. METHODS: Rice bran was extracted with dichloromethane and methanol. Chemical constituents in the extracts were analyzed by colorimetric assay and high performance liquid chromatography. The mutagenicity and antimutagenicity of the extracts were determined via the Salmonella mutation assay. The anticarcinogenic enzyme induction and antioxidant activities of the extracts were examined using Hepa1c1c7 cells and 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay, respectively. RESULTS: The methanol extracts of rice bran contained high amounts of phenolic acids, flavonoids, anthocyanins, and phytic acid, whereas large amounts of γ-oryzanol and vitamin E were presented in the dichloromethane extract. None of the extracts were mutagenic to Salmonella typhimurium. All rice bran extracts had strong antimutagenic effects against aflatoxin B1- and 2-amino-3,4-dimethylimidazo [4,5-f]quinoline-induced mutagenesis. The inhibitory effect against 2-aminofluorene-induced mutagenesis was found in the dichloromethane extract, while only the methanol extract of purple rice bran exhibited antimutagenic effects against benzo(a)pyrene. None of the extracts induced quinone reductase activity in Hepa1c1c7 cells. Additionally, the greatest antioxidant capacity was found in the methanol extract of purple rice bran. CONCLUSIONS: The methanol extract of purple rice bran containing high amount of phenolic acids, flavonoids, anthocyanins, and phytic acid showed the most effective antioxidant and antimutagenic activities by inhibiting mutagenic metabolizing enzymes and/or scavenging free radicals. These results demonstrate the nutritional and medical value of Thai rice for cancer prevention.
Aflatoxins ; Anthocyanins ; Antimutagenic Agents ; Asian Continental Ancestry Group* ; Benzo(a)pyrene ; Chromatography, Liquid ; Enzyme Induction ; Flavonoids ; Free Radicals ; Humans ; Methanol ; Methylene Chloride ; Mutagenesis ; NAD(P)H Dehydrogenase (Quinone) ; Phenol ; Phytic Acid ; Phytochemicals ; Salmonella ; Salmonella typhimurium ; Vitamin E ; Vitamins

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