BZD9L1 benzimidazole analogue hampers colorectal tumor progression by impeding angiogenesis  

作　　者：Chern Ein Oon Ayappa V Subramaniam Lik Yang Ooi Ashwaq Hamid Salem Yehya Yeuan Ting Lee Gurjeet Kaur Sreenivasan Sasidharan Beiying Qiu Xiaomeng Wang 

机构地区：[1]Institute for Research in Molecular Medicine,Universiti Sains Malaysia,Penang 11800,Malaysia [2]Cancer Research,Eman Biodiscoveries,Kedah 08000,Malaysia [3]Vatche and Tamar Division of Digestive Diseases,Department of Medicine,David Geffen School of Medicine at University of California Los Angeles,Los Angeles,CA 90095,United States [4]Academic Clinical Program,Duke-NUS Medical School,National University of Singapore,Singapore 169857,Singapore [5]Singapore National Eye Centre,Singapore Eye Research Institute,Singapore 168751,Singapore

出　　处：《World Journal of Gastrointestinal Oncology》2023年第5期810-827,共18页世界胃肠肿瘤学杂志（英文版）（电子版）

基　　金：Supported by the Ministry of Higher Education Malaysia for the Fundamental Research Grant Scheme,No. FRGS/1/2021/SKK06/USM/02/7

摘　　要：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 choroid

关 键 词：Colorectal cancer BZD9L1 SIRTUIN BENZIMIDAZOLE ANGIOGENESIS 

分 类 号：R735.3[医药卫生—肿瘤]