Gene expression-based chemical genomics identifies potential therapeutic drugs in hepatocellular carcinoma.
Gene expression-based chemical genomics identifies potential therapeutic drugs in hepatocellular carcinoma.
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DOI：
10.1371/journal.pone.0027186
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Huang CY
中科院分区：
文献类型：
--
作者：
Chen MH;Yang WL;Lin KT;Liu CH;Liu YW;Huang KW;Chang PM;Lai JM;Hsu CN;Chao KM;Kao CY;Huang CY
肝细胞癌是一种侵袭性肿瘤，预后差。目前，只有索拉非尼被FDA批准用于晚期肝癌的治疗，因此迫切需要寻找治疗肝癌的候选药物。我们假设，如果一种药物特征可以逆转至少部分地逆转肝细胞癌的基因表达特征，它可能具有抑制肝细胞癌相关途径从而治疗肝细胞癌的潜力。为了验证这一假设，我们首先建立了一个整合的平台--“肝细胞癌基因在线百科全书2”，名为EHCO2，以系统地收集、组织和比较来自肝细胞癌研究的公开数据。由此产生的集合包括总共4020个基因。为了系统地查询包含6,100个药物介导的表达谱的连通性图谱(Cmap)，我们进一步设计了各种基因签名选择和丰富方法，包括随机化技术、多数投票和集团分析。随后，50种首选药物中的28种，包括丹尼斯皮霉素、曲古菌素A、硫代鸟苷，以及几种具有抗肿瘤活性的抗精神病药物，通过在肝癌细胞系中的细胞存活率和克隆形成实验进行了验证。为了加速它们未来的临床应用，可能是通过药物再利用，我们选择了两种成熟的药物在小鼠身上进行测试，氯丙嗪和三氟拉嗪。两种药物均可抑制原位肝肿瘤的生长。总之，通过连接性图谱分析和实验室验证，我们成功地发现并验证了潜在用于肝癌治疗的现有药物，从而表明该程序在加快肝癌治疗的药物再利用方面是有用的。
Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis. Currently, only sorafenib is approved by the FDA for advanced HCC treatment; therefore, there is an urgent need to discover candidate therapeutic drugs for HCC. We hypothesized that if a drug signature could reverse, at least in part, the gene expression signature of HCC, it might have the potential to inhibit HCC-related pathways and thereby treat HCC. To test this hypothesis, we first built an integrative platform, the “Encyclopedia of Hepatocellular Carcinoma genes Online 2”, dubbed EHCO2, to systematically collect, organize and compare the publicly available data from HCC studies. The resulting collection includes a total of 4,020 genes. To systematically query the Connectivity Map (CMap), which includes 6,100 drug-mediated expression profiles, we further designed various gene signature selection and enrichment methods, including a randomization technique, majority vote, and clique analysis. Subsequently, 28 out of 50 prioritized drugs, including tanespimycin, trichostatin A, thioguanosine, and several anti-psychotic drugs with anti-tumor activities, were validated via MTT cell viability assays and clonogenic assays in HCC cell lines. To accelerate their future clinical use, possibly through drug-repurposing, we selected two well-established drugs to test in mice, chlorpromazine and trifluoperazine. Both drugs inhibited orthotopic liver tumor growth. In conclusion, we successfully discovered and validated existing drugs for potential HCC therapeutic use with the pipeline of Connectivity Map analysis and lab verification, thereby suggesting the usefulness of this procedure to accelerate drug repurposing for HCC treatment.
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影响因子：
4.2
作者：
Hoshida Y;Toffanin S;Lachenmayer A;Villanueva A;Minguez B;Llovet JM
通讯作者：
Llovet JM
影响因子：
14.9
作者：
Kuhn M;Szklarczyk D;Franceschini A;Campillos M;von Mering C;Jensen LJ;Beyer A;Bork P
通讯作者：
Bork P
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
5.7
作者：
Lan, Ming-Ying;Chen, Chi-Long;Huang, Chi-Ying F.
通讯作者：
Huang, Chi-Ying F.
影响因子：
6.2
作者：
Braconi, Chiara;Meng, Fanyin;Patel, Tushar
通讯作者：
Patel, Tushar