• Asian Pacific Journal of Cancer Prevention
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• 제17권3호
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• pp.1103-1110
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• 2016

In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.

• Biomolecules & Therapeutics
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• 제25권3호
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• pp.337-343
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• 2017

Kahweol as a coffee-specific diterpene has been reported to induce apoptosis in human cancer cells. Although some molecular targets for kahweol-mediated apoptosis have been elucidated, the further mechanism for apoptotic effect of kahweol is not known. Activating transcription factor 3 (ATF3) has been reported to be associated with apoptosis in colorectal cancer. The present study was performed to investigate the molecular mechanism by which kahweol stimulates ATF3 expression and apoptosis in human colorectal cancer cells. Kahweol increased apoptosis in human colorectal cancer cells. It also increased ATF3 expression through the transcriptional activity. The responsible cis-element for ATF3 transcriptional activation by kahweol was CREB located between -147 to -85 of ATF3 promoter. ATF3 overexpression increased kahweol-mediated cleaved PARP, while ATF3 knockdown attenuated the cleavage of PARP by kahweol. Inhibition of ERK1/2 and $GSK3{\beta}$ blocked kahweol-mediated ATF3 expression. The results suggest that kahweol induces apoptosis through ATF3-mediated pathway in human colorectal cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.6249-6256
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• 2013

One-carbon metabolism plays an important role in colorectal carcinogenesis. Meta-analyses have suggested protective associations of folate and vitamin $B_6$ intakes with colorectal cancer primarily based on studies in Caucasians, and genetic polymorphisms pertaining to the folate metabolism have been a matter of interest. Less investigated are the roles of methionine synthase (MTR) and thymidylate synthetase (TS) polymorphisms in colorectal carcinogenesis. In a study of 816 cases and 815 community controls in Japan, we investigated associations of dietary intakes of folate, methionine, vitamin $B_2$, vitamin $B_6$, and vitamin $B_{12}$ with colorectal cancer risk. The associations with MTR 2756A>G, MTRR 66A>G, and TSER repeat polymorphism were examined in 685 cases and 778 controls. Methionine and vitamin $B_{12}$ intakes were inversely associated with colorectal cancer risk, but the associations were totally confounded by dietary calcium and n-3 fatty acids. The other nutrients showed no association with the risk even without adjustment for calcium and n-3 fatty acids. The TSER 2R allele was dose-dependently associated with an increased risk. The MTR and MTRR polymorphisms were unrelated to colorectal cancer risk. There was no measurable gene-gene or gene-nutrient interaction, but increased risk associated with the TSER 2R allele seemed to be confined to individuals with high folate status. This study does not support protective associations for folate and vitamin $B_6$. The TSER 2R allele may confer an increased risk of colorectal cancer. The role of the TSER polymorphism in colorectal carcinogenesis may differ by ethnicity.

• Asian Pacific Journal of Cancer Prevention
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• 제15권13호
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• pp.5383-5387
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• 2014

Purpose: To investigate whether pretreatment serum carbohydrate antigen 19-9 (CA 19-9) levels are associated with pathological responses to preoperative chemoradiotherapy (CRT) in patients with rectal cancer. Materials and Methods: In total, 260 patients with locally advanced rectal cancer (cT3-4NanyM0) who underwent preoperative CRT and radical surgery were analyzed retrospectively. CRT consisted of 50.4 Gy pelvic radiotherapy and concurrent chemotherapy. Radical surgery was performed at a median of 7 weeks after CRT completion. Pathological CRT response criteria included downstaging (ypStage 0-I) and ypT0-1. A discrimination threshold of CA 19-9 level was determined using a receiver operating characteristics analysis. Results: The median CA 19-9 level was 8.0 (1.0-648.0) U/mL. Downstaging occurred in 94 (36.2%) patients and ypT0-1 in 50 (19.2%). The calculated optimal threshold CA 19-9 level was 10.2 U/mL for downstaging and 9.0 U/mL for ypT0-1. On multivariate analysis, CA 19-9 (${\leq}9.0U/mL$) was significantly associated with downstaging (odds ratio, 2.089; 95% confidence interval, 1.189-3.669; P=0.010) or ypT0-1 (OR, 2.207; 95%CI, 1.079-4.512; P=0.030), independent of clinical stage or carcinoembryonic antigen. Conclusions: This study firstly showed a significant association of pretreatment serum CA 19-9 levels with pathological CRT responses of rectal cancer. The CA 19-9 level is suggested to be valuable in predicting CRT responses of rectal cancer cases before treatment.

• Asian Pacific Journal of Cancer Prevention
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• 제15권17호
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• pp.7337-7341
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• 2014

Background: The physiological role of vitamin D extends beyond bone health and calcium-phosphate homeostasis to effects on cancer risk, mainly for colorectal cancer. Vitamin D may have an anticancer effect in colorectal cancer mediated by binding of the active form $1,25(OH)_2D$ to the vitamin D receptor (VDR). The Taq1 VDR gene polymorphism, a C-to-T base substitution (rs731236) in exon 9 may influence its expression and function. The aim of this study wass to determine the 25(OH)D vitamin D level and to investigate the association between circulating vitamin D level and Taq1VDR gene polymorphism among Jordanian colorectal cancer patients. Materials and Methods: This case control study enrolled ninety-three patients and one hundred and two healthy Jordanian volunteers from AL-Basheer Hospital/Amman (2012-2013). Ethical approval and signed consent forms were obtained from all participants before sample collection. 25(OH)D levels were determined by competitive immunoassay Elecsys (Roche Diagnostic, France). DNA was extracted (Promega, USA) and amplified by PCR followed by VDR Taq1 restriction enzyme digestion. The genotype distribution was evaluated by paired t-test and chi-square. Comparison between vitamin D levels among CRC and control were assessed by odds ratio with 95% confidence interval. Results: The vitamin D serum level was significantly lower among colorectal cancer patients (8.34 ng/ml) compared to the healthy control group (21.02ng/ml). Patients deficient in vitamin D (less than 10.0 ng/ml) had increased colorectal cancer risk 19.2 fold compared to control. Only 2.2% of CRC patients had optimal vitamin D compared to 23.5% among healthy control. TT, Tt and tt Taq1 genotype frequencies among CRC cases was 35.5%, 50.5% and 14% compared to 43.1%, 41.2% and 15.7% among healthy control; respectively. CRC patients had lower mean vitamin D level among TT ($8.91{\pm}4.31$) and Tt ($9.15{\pm}5.25$) genotypes compared to control ($21.3{\pm}8.31$) and ($19.3{\pm}7.68$); respectively. Conclusions: There is significant association between low 25(OH)D serum level and colorectal cancer risk. The VDRTaq1 polymorphism was associated with increased colorectal cancer risk among patient with VDRTaq1 TT and Tt genotypes. Understanding the functional mechanism of VDRTaq1 TT and Tt may provide a strategy for colorectal cancer prevention and treatment.

• Asian Pacific Journal of Cancer Prevention
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• 제15권18호
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• pp.7653-7664
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• 2014

Background: Colorectal ranked first among cancers reported in males and ranked second amongst females in Jordan, accounting for 12.7% and 10.5% of cancers in males and females, respectively. Colorectal cancer patients can suffer several consequences after treatment that include pain and fatigue, constipation, stoma complications, sexual problems, appearance and body-image concerns as well as psychological dysfunction. There is no published quantitative data on the health-related quality of life and psychological wellbeing of Jordanian colorectal cancer survivors. Method: This project was a cross-sectional study of colorectal cancer survivors diagnosed in 2009 and 2010. Assessment was performed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the colorectal cancer specific module (EORTC QLQ-CR 29) and the Hospital Anxiety and Depression Scale (HADS). Data on potential predictors of scores were also collected. Results: A total of 241 subjects completed the study with mean age of $56.7{\pm}13.6$. Males represented 52.3% of study participants. A majority of participants reported good to high overall health; the mean Global health score was $79.74{\pm}23.31$ with only 6.64% of study participants scoring less than 33.3%. The striking result in this study was that none of the study participants participated in a psychosocial support group; only 4 of them (1.7%) were even offered such support. The mean scores for HADS, depression score, and anxiety score were $8.25{\pm}9$, $4.35{\pm}4.9$ and $3.9{\pm}4.6$, respectively. However, 77.1% of study participants were within the normal category for the depression score and 81.7% were within this category for anxiety score; 5.4% of participants had severe anxiety and 5.4% of them had severe depression. Discussion: Patients with colorectal cancer in Jordan have a good quality of life and psychological wellbeing scores when compared with patients from western countries. None of the colorectal cancer patients managed at the Ministry of Health received any formal counselling, or participated in psychological or social support programmes. This highlights the urgent need for a psychosocial support programme, psychological screening and consultations for patients diagnosed with colorectal cancer at the Ministry of Health Hospitals.

• BMB Reports
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• 제44권5호
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• pp.317-322
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• 2011

Hereditary non-polyposis Colorectal Cancer (HNPCC) is an autosomal dominant inheritance syndrome. HNPCC is the most common hereditary variant of colorectal cancer (CRC), which accounts for 2-5% CRCs, mainly due to hMLH1 and hMSH2 mutations that impair DNA repair functions. Our study aimed to identify the patterns of hMSH2 and hMLH1 mutations in Chinese HNPCC patients. Ninety-eight unrelated families from China meeting Amsterdam or Bethesda criteria were included in our study. Germline mutations in MLH1 and MSH2 genes, located in the exons and the splice-site junctions, were screened in the 98 probands by direct sequencing. Eleven mutations were found in ten patients (11%), with six in MLH1 (54.5%) and five in MSH2 (45.5%) genes. One patient had mutations in both MLH1 and MSH2 genes. Three novel mutations in MLH1 gene (c.157_160delGAGG, c.2157dupT and c.-64G>T) were found for the first time, and one suspected hotspot in MSH2 (c.1168C>T) was revealed.

• Asian Pacific Journal of Cancer Prevention
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• 제16권3호
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• pp.1069-1072
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• 2015

Background: Colorectal cancer (CRC) is an important cause of mortality and morbidity in many communities worldwide. This population based study was conducted to assess determinants of colorectal mortality in Iranian patients. Materials and Methods: A cohort of 1,127 cases of confirmed colorectal cancer registered in a population based registry covering 10 referral hospital in Tehran, Iran, were followed for five years. Information about tumor characteristics, smoking status and family history were collected at base line and survival status were followed every six months by contacting patient or next of kin (if patients died during the follow-up). The cause of death for each case was validated by verbal autopsy and referring to patient medical records at the time of death. The data were analyzed by Stata software using univariate and multivariate analysis (Cox regression). In building the model a p value of less than 5% was considered as significant. Results: The age at diagnosis was $53.5{\pm}14$ years. Sixty one percent were male. Colorectal mortality among the patients was 96.9 person-years among men and 83 person-years among women. Seventy five percent of patients lived for 2.72 years, 50% for 5.83, and 25% for 13 years after the diagnosis of colorectal cancer. The age at diagnosis was significantly different between men and women (p<0.03). Higher tumor grade predicted higher death rate; the adjusted hazard ratios were 1.79 (95%CI, 0.88-3.61), 2.16 (95%CI, 1.07-4.37), and 3.1 (95%CI, 1.51-6.34) for grades II, III, and IV respectively when they were compared with grade I as reference. Ethnicity, marital status, family history of cancer, and smoking were related to survival with different degrees of magnitude. Conclusions: Among many factors related to survival among the colorectal patients, tumor grade and smoking showed the highest magnitudes of association.

• Asian Pacific Journal of Cancer Prevention
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• 제15권11호
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• pp.4595-4599
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• 2014

Background: Colorectal cancer is a serious health problem. Early detection of colorectal cancer is crucial for treatment and reducing mortality. Beliefs related to colorectal cancer have been found to be a factor in a person's decision about colorectal cancer screening programs. To determine such beliefs, a valid and reliable instrument is necessary. Objective:The aim of this study was to adapt and determine the psychometric properties of the Persian version of Champion's Health Belief Model Scale of breast cancer screening in the measurement of beliefs toward colorectal cancer (CRC) screening. Materials and Methods: The 'forward-backward' procedure was applied to translate the instrument from English into Persian. This study was conducted in Iran from June 2012 to May 2013. A convenience sample of 200 individuals aged 50 years and older was recruited from the population at the outpatient clinics in the three teaching hospitals. Validity was assessed using content, face and construct validity. To test reliability, the internal consistency was assessed by using Cronbach's alpha coefficient and test-retest (intraclass correlation coefficient) analyses. Exploratory factor analysis was used to assess the construct validity and determine the factors of adapted Champion's Health Belief Model Scale. Results: The mean age of the participants were 62.5 years (SD=10.8 years) and the majority of them (75.5 percent) were female. The results of exploratory factor analysis indicated a six-factor solution for the questionnaire (benefits, motivation and confidence, seriousness, susceptibility, emotional barriers and background barriers) that jointly accounted for 55.52% of variance observed. Cronbach's alpha of the subscales ranged from 0.57 to 0.89 and test-retest reliability ranged from 0.81 to 0.93 indicating a good range of reliability. Conclusions: The findings of this study suggest that the Persian version of Champion's Health Belief Model Scale of CRC screening has good psychometric properties and could be an appropriate measure for health beliefs related to CRC screening in national and international studies.

• Asian Pacific Journal of Cancer Prevention
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• 제15권21호
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• pp.9185-9190
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• 2014

Cyclo-oxygenase-2(Cox-2), a key regulator of inflammation-producing prostaglandins, promotes cell proliferation and growth. Therefore, a better understanding of the regulatory mechanisms of Cox-2 could lead to novel targeted cancer therapies. MicroRNAs are strongly implicated in colorectal cancer but their specific roles and functions have yet to be fully elucidated. MiR-1297 plays an important role in lung adenocarcinoma and laryngeal squamous cell carcinoma, but its significance in colorectal cancer (CRC) has yet to be reported. In our present study, we found miR-1297 to be down regulated in both CRC-derived cell lines and clinical CRC samples, when compared with normal tissues. Furthermore, miR-1297 could inhibit human colorectal cancer LOVO and HCT116 cell proliferation, migration, and invasion in vitro and tumorigenesis in vivo by targeting Cox-2. Moreover, miR-1297 directly binds to the 3'-UTR of Cox-2, and the expression level was drastically decreased in LOVO and HCT116 cells following overexpression of miR-1297. Additionally, Cox-2 expression levels are inversely correlated with miR-1297 expression in human colorectal cancer xenograft tissues. These results imply that miR-1297 has the potential to provide a new approach to colorectal cancer therapy by directly inhibiting Cox-2 expression.