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BZD9L1 benzimidazole analogue hampers colorectal tumor progression by impeding angiogenesis

World Journal of Gastrointestinal Oncology 2023年第5期15卷 810-827页

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 Institute for Research in Molecular Medicine Universiti Sains MalaysiaPenang 11800Malaysia Cancer Research Eman BiodiscoveriesKedah 08000Malaysia Vatche and Tamar Division of Digestive Diseases Department of MedicineDavid Geffen School of Medicine at University of California Los AngelesLos AngelesCA 90095United States Academic Clinical Program Duke-NUS Medical SchoolNational University of SingaporeSingapore 169857Singapore Singapore National Eye Centre Singapore Eye Research InstituteSingapore 168751Singapore

BACKGROUND The development of new vasculatures(angiogenesis)is indispensable in supplying oxygen and nutrients to fuel tumor *** dysregulation in the tumor vasculature is critical to colorectal cancer(CRC)***(SIRT)enzymes are highly expressed in blood ***9L1 benzimidazole analogue is a SIRT 1 and 2 inhibitor with reported anticancer activities in ***,its role has yet to be explored in CRC tumor *** To investigate the anti-angiogenic potential of BZD9L1 on endothelial cells(EC)in vitro,ex vivo and in HCT116 CRC xenograft in vivo *** ***926 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 ***,2.5μM and 5.0μM of BZD9L1 were employed in downstream in vitro assays,including cell cycle,cell death and sprouting in *** 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 *** co-culture with HCT116 CRC cells was performed to investigate the impact of growth factors modulated by BZD9L1-treated EC on *** effect of BZD9L1 on sprouting impediment and vessel regression was determined using mouse ***116 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,*** 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 *** compound also arrested the cells at G1 phase and i

关键词： Colorectal cancer BZD9L1 Sirtuin Benzimidazole Angiogenesis

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