Inhibition of Sp1-dependent transcription and antitumor activity of the new aureolic acid analogues mithramycin SDK and SK in human ovarian cancer xenografts.
Inhibition of Sp1-dependent transcription and antitumor activity of the new aureolic acid analogues mithramycin SDK and SK in human ovarian cancer xenografts.
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DOI：
10.1016/j.ygyno.2010.03.020
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发表时间：
2010-08-01
影响因子：
4.7
通讯作者：
Catapano CV
中科院分区：
文献类型：
--
作者：
Previdi S;Malek A;Albertini V;Riva C;Capella C;Broggini M;Carbone GM;Rohr J;Catapano CV
Sp家族转录因子的活性增加是癌症发生和发展中的常见和关键事件。控制肿瘤生长、侵袭和血管生成的基因受Sp因子（如Sp1、Sp3或Sp 4）调节，并且在肿瘤中经常过表达。靶向Sp因子已被探索作为一种治疗方法。Mithramycin（MTM）是一种天然抗生素，可结合DNA并抑制Sp1依赖性转录。新的类似物，命名为MTM-SDK和MTM-SK，最近获得的MTM生物合成途径的基因工程，并已证明在卵巢癌细胞系在体外提高转录和抗增殖活性。在本研究中，我们评估了新化合物在人卵巢癌异种移植物中的活性。通过免疫组化评估卵巢癌标本和肿瘤异种移植物中Sp1和靶蛋白的表达。通过定量RT-PCR评估细胞和肿瘤异种移植物样品中Sp1调节基因的药物诱导沉默。在健康和荷瘤免疫功能低下小鼠中分别研究了化合物的毒性和抗肿瘤活性。Sp1在卵巢上皮性癌中表达增高。MTM-SDK和MTM-SK在体外和肿瘤异种移植物中均作为Sp1依赖性转录的有效抑制剂。即使在长期给药和卵巢肿瘤异种移植物生长延迟后，两种化合物的耐受性也很好。MTM-SDK对原位肿瘤特别有效，导致存活率显著增加和肿瘤进展延迟。MTM-SDK和MTM-SK在体内显示出相关活性，并代表了用于治疗卵巢癌的感兴趣的候选物。
Increased activity of Sp family of transcription factors is a frequent and critical event in cancer development and progression. Genes governing tumor growth, invasion and angiogenesis are regulated by Sp factors, like Sp1, Sp3 or Sp4, and are frequently over-expressed in tumors. Targeting Sp factors has been explored as a therapeutic approach. Mithramycin (MTM) is a natural antibiotic that binds DNA and inhibit Sp1-dependent transcription. New analogues, named MTM-SDK and MTM-SK, were recently obtained by genetic engineering of the MTM biosynthetic pathway and have demonstrated improved transcriptional and antiproliferative activity in ovarian cancer cell lines in vitro. In present study we evaluated the activity of the new compounds in human ovarian cancer xenografts. Expression of Sp1 and target proteins in ovarian cancer specimens and tumor xenografts was assessed by immunohistochemistry. Drug –induced silencing of Sp1-regulated genes in cells and tumor xenograft samples was assessed by quantitative RT-PCR. Toxicity and antitumor activity of the compounds were investigated in healthy and tumor-bearing immunocompromised mice, respectively. Expression of Sp1 was frequently increased in human epithelial ovarian cancers. MTM-SDK and MTM-SK acted as potent inhibitors of Sp1-dependent transcription both in vitro and in tumor xenografts. Both compounds were well tolerated even after prolonged administration and delayed growth of ovarian tumor xenografts. MTM-SDK was particularly effective against orthotopic tumors leading to a significant increase of survival and delay of tumor progression. MTM-SDK and MTM-SK show relevant activity in vivo and represent interesting candidates for treatment of ovarian cancers.
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影响因子：
14.9
作者：
Barceló F;Scotta C;Ortiz-Lombardía M;Méndez C;Salas JA;Portugal J
通讯作者：
Portugal J
影响因子：
11.2
作者：
Chadalapaka G;Jutooru I;Chintharlapalli S;Papineni S;Smith R 3rd;Li X;Safe S
通讯作者：
Safe S
DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
11.2
作者：
Chintharlapalli, Sudhakar;Papineni, Sabitha;Safe, Stephen
通讯作者：
Safe, Stephen
影响因子：
15.9
作者：
BLUME, SW;SNYDER, RC;MILLER, DM
通讯作者：
MILLER, DM