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BZD9L1 benzimidazole analogue hampers colorectal tumor progression by impeding angiogenesis 被引量:1
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作者 chern ein oon Ayappa V Subramaniam +6 位作者 Lik Yang Ooi Ashwaq Hamid Salem Yehya Yeuan Ting Lee Gurjeet Kaur Sreenivasan Sasidharan Beiying Qiu Xiaomeng Wang 《World Journal of Gastrointestinal Oncology》 SCIE 2023年第5期810-827,共18页
BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CR... BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor growth.Epigenetic dysregulation in the tumor vasculature is critical to colorectal cancer(CRC)progression.Sirtuin(SIRT)enzymes are highly expressed in blood vessels.BZD9L1 benzimidazole analogue is a SIRT 1 and 2 inhibitor with reported anticancer activities in CRC.However,its role has yet to be explored in CRC tumor angiogenesis.AIM To investigate the anti-angiogenic potential of BZD9L1 on endothelial cells(EC)in vitro,ex vivo and in HCT116 CRC xenograft in vivo models.METHODS EA.hy926 EC were treated with half inhibitory concentration(IC50)(2.5μM),IC50(5.0μM),and double IC50(10.0μM)of BZD9L1 and assessed for cell proliferation,adhesion and SIRT 1 and 2 protein expression.Next,2.5μM and 5.0μM of BZD9L1 were employed in downstream in vitro assays,including cell cycle,cell death and sprouting in EC.The effect of BZD9L1 on cell adhesion molecules and SIRT 1 and 2 were assessed via real-time quantitative polymerase chain reaction(qPCR).The growth factors secreted by EC post-treatment were evaluated using the Quantibody Human Angiogenesis Array.Indirect co-culture with HCT116 CRC cells was performed to investigate the impact of growth factors modulated by BZD9L1-treated EC on CRC.The effect of BZD9L1 on sprouting impediment and vessel regression was determined using mouse choroids.HCT116 cells were also injected subcutaneously into nude mice and analyzed for the outcome of BZD9L1 on tumor necrosis,Ki67 protein expression indicative of proliferation,cluster of differentiation 31(CD31)and CD34 EC markers,and SIRT 1 and 2 genes via hematoxylin and eosin,immunohistochemistry and qPCR,respectively.RESULTS BZD9L1 impeded EC proliferation,adhesion,and spheroid sprouting through the downregulation of intercellular adhesion molecule 1,vascular endothelial cadherin,integrin-alpha V,SIRT1 and SIRT2 genes.The compound also arrested the cells at G1 phase and induced apoptosis in the EC.In mouse choroids,BZD9L1 inhibited sprouting and regressed sprouting vessels compared to the negative control.Compared to the negative control,the compound also reduced the protein levels of angiogenin,basic fibroblast growth factor,platelet-derived growth factor and placental growth factor,which then inhibited HCT116 CRC spheroid invasion in co-culture.In addition,a significant reduction in CRC tumor growth was noted alongside the downregulation of human SIRT1(hSIRT1),hSIRT2,CD31,and CD34 EC markers and murine SIRT2 gene,while the murine SIRT1 gene remained unaffected,compared to vehicle control.Histology analyses revealed that BZD9L1 at low(50 mg/kg)and high(250 mg/kg)doses reduced Ki-67 protein expression,while BZD9L1 at the high dose diminished tumor necrosis compared to vehicle control.CONCLUSION These results highlighted the anti-angiogenic potential of BZD9L1 to reduce CRC tumor progression.Furthermore,together with previous anticancer findings,this study provides valuable insights into the potential of BZD9L1 to co-target CRC tumor vasculatures and cancer cells via SIRT1 and/or SIRT2 down-regulation to improve the therapeutic outcome. 展开更多
关键词 Colorectal cancer BZD9L1 SIRTUIN BENZIMIDAZOLE ANGIOGENESIS
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Anti-tumour activity and toxicological studies of combination treatment of Orthosiphon stamineus and gemcitabine on pancreatic xenograft model
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作者 Ashwaq Hamid Salem Yehya Ayappa V Subramaniam +3 位作者 Muhammad Asif Gurjeet Kaur Amin M S Abdul Majid chern ein oon 《World Journal of Gastroenterology》 SCIE CAS 2022年第32期4620-4634,共15页
BACKGROUND Pancreatic cancer is the most aggressive cancer type.Gemcitabine is the first line chemo-drug used for pancreatic cancer but exerts a broad spectrum of organ toxicities and adverse effects in patients.AIM T... BACKGROUND Pancreatic cancer is the most aggressive cancer type.Gemcitabine is the first line chemo-drug used for pancreatic cancer but exerts a broad spectrum of organ toxicities and adverse effects in patients.AIM To evaluate the anti-tumour activity and toxicological effects of Orthosiphon stamineus extract formulation(ID:C5EOSEW5050ESA trademarked as Nuvastatic^(TM)),and gemcitabine combination on pancreatic xenograft model.METHODS Mice were randomly divided into six groups of 6 mice each(n=6)and given different treatments for 28 d.The study design consisted of a 2 x 3 factorial treatment structure,with gemcitabine(yes/no)by oral(at 1200 and 400 mg/kg per day).Human pancreatic cancer cells were injected subcutaneously into the flanks of athymic nude mice.C5EOSEW5050ESA(200 or 400 mg/kg per day)was administered orally,while gemcitabine(10 mg/kg per 3 d)was given intraperitoneally either alone or in combination treatment.Histopathological analyses of vital organs,tumour tissues,and incidence of lethality were analysed.Analyses of tumour necrosis and proliferation were determined by haematoxylin-eosin staining and immunohistochemistry for Ki-67,respectively.RESULTS No signs of toxicity or damage to vital organs were observed in all treatment groups compared to the untreated group.C5EOSEW5050ESA at 200 mg/kg and gemcitabine combination had no additive antitumor effects compared to a single treatment.Remarkably,a comparably greater response in a reduction in tumour growth,Ki-67 protein expression,and necrosis was demonstrated by 400 mg/kg of C5EOSEW5050ESA and gemcitabine combination than that of the individual agents.CONCLUSION These results highlighted the synergistic activity of C5EOSEW5050ESA with gemcitabine to reduce pancreatic tumour growth in mice compared to a single treatment.Thus,this study provides valuable insights into using C5EOSEW5050ESA as a complementary treatment with gemcitabine for pancreatic cancer. 展开更多
关键词 Pancreatic cancer Orthosiphon stamineus C5EOSEW5050ESA GEMCITABINE Complementary medicine
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Benzimidazole and its derivatives as cancer therapeutics:The potential role from traditional to precision medicine
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作者 Yeuan Ting Lee Yi Jer Tan chern ein oon 《Acta Pharmaceutica Sinica B》 SCIE CAS CSCD 2023年第2期478-497,共20页
Cancer is the second leading cause of mortality globally which remains a continuing threat to human health today.Drug insensitivity and resistance are critical hurdles in cancer treatment;therefore,the development of ... Cancer is the second leading cause of mortality globally which remains a continuing threat to human health today.Drug insensitivity and resistance are critical hurdles in cancer treatment;therefore,the development of new entities targeting malignant cells is considered a high priority.Targeted therapy is the cornerstone of precision medicine.The synthesis of benzimidazole has garnered the attention of medicinal chemists and biologists due to its remarkable medicinal and pharmacological properties.Benzimidazole has a heterocyclic pharmacophore,which is an essential scaffold in drug and pharmaceutical development.Multiple studies have demonstrated the bioactivities of benzimidazole and its derivatives as potential anticancer therapeutics,either through targeting specific molecules or non-gene-specific strategies.This review provides an update on the mechanism of actions of various benzimidazole derivatives and the structure-activity relationship from conventional anticancer to precision healthcare and from bench to clinics. 展开更多
关键词 Benzimidazole derivatives Targeted therapy ANTICANCER Precision medicine
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Mesuaferrea stem bark extract induces apoptosis and inhibits metastasis in human colorectal carcinoma HCT 116 cells, through modulation of multiple cell signalling pathways 被引量:2
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作者 Muhammad Asif Armaghan Shafaei +5 位作者 Aman Shah Abdul Majid Mohammed Oday Ezzat Saad S Dahham Mohamed B.Khadeer Ahamed chern ein oon Amin Malik Shah Abdul Majid 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2017年第7期505-514,共10页
Considering the great potential of natural products as anticancer agents, the present study was designed to explore the molecular mechanisms responsible for anticancer activities of Mesua ferrea stem bark extract agai... Considering the great potential of natural products as anticancer agents, the present study was designed to explore the molecular mechanisms responsible for anticancer activities of Mesua ferrea stem bark extract against human colorectal carcinoma. Based on MTT assay results, bioactive sub-fraction(SF-3) was selected for further studies using HCT 116 cells. Repeated column chromatography resulted in isolation of less active α-amyrin from SF-3, which was identified and characterized by GC-MS and HPLC methods. α-amyrin and betulinic acid contents of SF-3 were measured by HPLC methods. Fluorescent assays revealed characteristic apoptotic features, including cell shrinkage, nuclear condensation, and marked decrease in mitochondrial membrane potential in SF-3 treated cells. In addition, increased levels of caspases-9 and-3/7 levels were also observed in SF-3 treated cells. SF-3 showed promising antimetastatic properties in multiple in vitro assays. Multi-pathway analysis revealed significant down-regulation of WNT, HIF-1α, and EGFR with simultaneous up-regulation of p53, Myc/Max, and TGF-β signalling pathways in SF-3 treated cells. In addition, promising growth inhibitory effects were observed in SF-3 treated HCT 116 tumour spheroids, which give a hint about in vivo antitumor efficacy of SF-3 phytoconstituents. In conclusion, these results demonstrated that anticancer effects of SF-3 towards colon cancer are through modulation of multiple molecular pathways. 展开更多
关键词 Mesua ferrea a-Amyrin APOPTOTIC Antimetastatic Molecular PATHWAYS
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