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Overcoming chemoresistance in non-angiogenic colorectal cancer by metformin via inhibiting endothelial apoptosis and vascular immaturity

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Journal of Pharmaceutical Analysis 2023年第3期13卷 262-275页

作者： Guang-Yue Li Shu-Jing Zhang Dong Xue Yue-Qi Feng Yan Li Xun Huang Qiang Cui Bo Wang Jun Feng Tao Bao Pei-Jun Liu Shao-Ying Lu Ji-Chang Wang Department of Science and Technology The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Department of Vascular Surgery The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Department of General Surgery The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Center for Translational Medicine The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an710061China Department of Pharmacy Xi'an Jiaotong University Health Science CenterXi'an710061China

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer(CRC).In this study,we identified reduced microvessel density(MVD)and vascular immaturity resulting from endothelial apoptosis as therapeutic targets for overcoming chemoresistance.We focused on the effect of metformin on MVD,vascular maturity,and endothelial apoptosis of CRCs with a non-angiogenic phenotype,and further investigated its effect in overcoming chemoresistance.In situ transplanted cancer models were established to compare MVD,endothelial apoptosis and vascular maturity,and function in tumors from metformin-and vehicle-treated mice.An in vitro co-culture system was used to observe the effects of metformin on tumor cell-induced endothelial apoptosis.Transcriptome sequencing was performed for genetic screening.Non-angiogenic CRC developed independently of angiogenesis and was characterized by vascular leakage,immaturity,reduced MVD,and non-hypoxia.This phenomenon had also been observed in human CRC.Furthermore,non-angiogenic CRCs showed a worse response to chemotherapeutic drugs in vivo than in vitro.By suppressing endothelial apoptosis,metformin sensitized non-angiogenic CRCs to chemo-drugs via elevation of MVD and improvement of vascular maturity.Further results showed that endothelial apoptosis was induced by tumor cells via activation of caspase signaling,which was abrogated by metformin administration.These findings provide pre-clinical evidence for the involvement of endothelial apoptosis and subsequent vascular immaturity in the chemoresistance of non-angiogenic CRC.By suppressing endothelial apoptosis,metformin restores vascular maturity and function and sensitizes CRC to chemotherapeutic drugs via a vascular mechanism.

关键词： Metformin Colorectal cancer Non-angiogenic endothelial apoptosis Vascular immaturity

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Protective Effects of Silybin on Human Umbilical Vein endothelial Cell Injury induced by H2O2 in vitro

Protective Effects of Silybin on Human Umbilical Vein Endoth...

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2004年浙江省心血管病学学术年会

作者：黄兆铨汪云开 Department of cardiology ZheJiang Hospital of Traditional Chinese MedicineHangzhou310006

Oxidative injury induces cellular and nuclear damage that leads to cell injury.Agents orantioxidants that can inhibit production of reactive oxygen species can prevent injury.We tested thehypothesis that silybin can inhibit HO-induced injury in human umbilical vein endothelial cells.18 hrtreatment with 750 μmol/L HO significantly stimulated activation of caspase-3 and the resulted apoptosis.In addition,it is observed that HO increased the contents of MDA,the dehydrogenase (LDH) leakage,accompanied by the decrease in the content of NO in ECV-304 cells.In the HO apoptosis model,theaddition of 6.25-25mg/L of silybin which have in vitro radical scavenging activity,partially restored cellviability with a reduction in HO-induced apoptotic DNA damage,and partially inhibited the activation ofcaspase-3.Morever,it decreased other HO-induced changes in a concentration-dependent manner.Theendothelial cells apoptosis were detected by AO/EB dual staining as well as flow cytometry,and theactivity of pro-apoptotic factor csaepase-3 were detected by immunohistochemical method.Our resultssuggest that the antioxidants,silybin,protects ECV-304 cells against HO-induced injury probably throughantioxidation,the increasing of the concentration of NO and the inhibiting of signaling pathways mediatedby caspase-3.Thus,inhibition of caspase-3 activation by silybin may imply its usefulness for prevention and/or treatment of endothelial cell dysfunction,which was suggested to be the first step in thedevelopment of atherosclerosis and other cardiological diseases.

关键词： Silybin endothelial apoptosis Hydrogen peroxide Caspase-3

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