邹敏;李锐峰;陈岷;颜晓燕;史惠卿;

• 1:成都医学院药学院
• 2:四川省医学科学院四川省人民医院药学部
• 3:中国人民解放军西部战区总医院

摘要(Abstract)：

采用药物重定位(Drug repositioning,DR)策略预测多发性骨髓瘤的候选化合物,为多发性骨髓瘤的治疗提供新的思路和方向。利用GEO数据库检索并筛选多发性骨髓瘤表达谱芯片数据,GEO2R软件提取差异表达基因(DEGs);DAVID和Panther数据库对差异表达基因进行富集和通路分析;利用STRING数据库构建蛋白-蛋白相互作用网络分析;将差异表达基因导入CMAP连接图,计算获得治疗MM的候选化合物,进一步对候选化合物进行查找和分析。结果显示:共获得差异表达基因53个,包括上调差异表达基因10个、下调差异表达基因43个;GO分析结果表明生物学过程涉及22个功能簇,分子功能涉及5个功能簇,细胞成分涉及5个功能簇;KEGG分析涉及10条通路;蛋白-蛋白相互作用网络分析显示VCAM1、CCR2、CCL3和CXCL12等4个基因为富集程度最高的核心差异表达基因;通过CMAP连接图计算得到排名前20的候选化合物,其中LY-294002和Tanespimycin可能对MM有潜在治疗作用,但还有待深入试验研究和临床验证。

关键词(KeyWords)： 药物重定位;多发性骨髓瘤;差异表达基因;候选化合物;生物信息学

Abstract:

Keywords:

基金项目(Foundation): 成都医学院校基金科研项目(编号20180376)

作者(Author): 邹敏;李锐峰;陈岷;颜晓燕;史惠卿;

Email:

DOI:

参考文献(References)：

• [1]ZWEEGMAN S,PALUMBO A,BRINGHEN S,et al.Age and aging in blood disorders:multiple myeloma[J].Haematologica,2014,99(7):1133-1137.
• [2]SIEGEL R L,MILLER K D,Jemal A.Cancer statistics,2016[J].CA:A Cancer Journal for Clinicians,2016,66(1):7-30.
• [3]CHEN G,XU Z,CHANG G,et al.The blueberry component pterostilbene has potent anti-myeloma activity in bortezomib-resistant cells[J].Oncology Reports,2017,38(1):488-496.
• [4]HANSFORD B G,SILBERMANN R.Advanced imaging of multiple myeloma bone disease[J].Front Endocrinol (Lausanne),2018,9:436.
• [5]KUMAR A K,DAKHIL C,Teeka SATYAN M,et al.Extramedullary progression of multiple myeloma despite concomitant medullary response to multiple combination therapies and autologous transplant:a case report[J].Journal of Medical Case Reports,2014,8:299.
• [6]PULLEY J M,RHOADS J P,JEROME R N,et al.Using what we already have:uncovering new drug repurposing strategies in existing omics data[J].Annual Review of Pharmacology and Toxicology,2019,18:16.
• [7]WANG F,LEI X,WU F X.A review of drug repositioning based chemical-induced cell line expression data[J].Current Medicinal Chemistry,2018,25(1):42.
• [8]GONCALVES V,PEREIRA J F S,JORDAN P.Signaling pathways driving aberrant splicing in cancer cells[J].Genes (Basel),2017,9(1):313.
• [9]HARVEY RD,LONIAL S.PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma[J].Future Oncology,2007,3(6):639-647.
• [10]HE J,LIU Z,ZHENG Y,et al.p38 MAPK in myeloma cells regulates osteoclast and osteoblast activity and induces bone destruction[J].Cancer Research,2012,72(24):6393-6402.
• [11]ZHANG K,XU Z,SUN Z.Identification of the key genes connected with plasma cells of multiple myeloma using expression profiles[J].OncoTargets and Therapy,2015,8:1795-1803.
• [12]VANDE BROEK I,LELEU X,SCHOTS R,et al.Clinical significance of chemokine receptor (CCR1,CCR2 and CXCR4) expression in human myeloma cells:the association with disease activity and survival[J].Haematologica,2006,91(2):200-206.
• [13]CONIGLIO S J.Role of tumor-derived chemokines in osteolytic bone metastasis[J].Front Endocrinol (Lausanne),2018,9:313.
• [14]DUENA-GONZALEZ A,CORONEL J,CETINA L,et al.Hydralazine-valproate:a repositioned drug combination for the epigenetic therapy of cancer[J].Expert Opinion on Drug Metabolism & Toxicology,2014,10(10):1433-1444.
• [15]ROCCARO A M,SACCO A,PURSCHKE W G,et al.SDF-1 inhibition targets the bone marrow niche for cancer therapy[J].Cell Reports,2014,9(1):118-128.
• [16]SAFAROGHL-AZAR A,BASHASH D,KAZEMI A,et al.Anticancer effect of pan-PI3K inhibitor on multiple myeloma cells:shedding new light on the mechanisms involved in BKM120 resistance[J].European Journal of Pharmacology,2018,842(2019):89-98.
• [17]CHEN P,WEN X,WANG B,et al.PI3K/Akt inhibitor LY294002 potentiates homoharringtonine antimyeloma activity in myeloma cells adhered to stromal cells and in SCID mouse xenograft[J].Annals Hematology,2018,97(5):865-875.
• [18]WANG Y Q,LIN Y,ZHAO J D,et al.Inhibitory effect of LY294002 on proliferation of multiple myeloma cells and its mechanism[J].Zhongguo Shi Yan Xue Ye Xue Za Zhi,2017,25(4):1092-1096.
• [19]NECHERS L,WORKMAN P.Hsp90 molecular chaperone inhibitors:are we there yet[J] Clinical Cancer Research,2012,18(1):64-76.
• [20]DIMOPOULOS M A,MITSIADES C S,ANDERSON K C,et al.Tanespimycin as antitumor therapy[J].Clinical Lymphoma Myeloma & Leukemia,2011,11(1):17-22.