Identification of repurposed small molecule drugs for chordoma therapy.
Identification of repurposed small molecule drugs for chordoma therapy.
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DOI：
10.4161/cbt.24596
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发表时间：
2013-07
影响因子：
3.6
通讯作者：
Austin CP
中科院分区：
文献类型：
--
作者：
Xia M;Huang R;Sakamuru S;Alcorta D;Cho MH;Lee DH;Park DM;Kelley MJ;Sommer J;Austin CP
脊索瘤是一种罕见的，生长缓慢的恶性肿瘤，起源于胎儿脊索的残余。手术是治疗脉络膜炎的首选，其次是放射治疗，尽管术后并发症仍然很严重。由于肿瘤位置的解剖结构和初次手术时侵犯肿瘤边缘，疾病经常复发。目前，没有有效的药物可用于患有脉络膜炎的患者。由于这种疾病的罕见性，在临床试验中测试药剂的机会有限，并且在制药工业中没有共同努力开发用于霍乱的药剂。为了快速有效地鉴定抑制脉络膜细胞生长的小分子，我们筛选了NCGC Pharmaceutical Collection（NPC），其中包含约2800种临床批准和研究药物，在脉络膜细胞系U-CH 1和U-CH 2中具有15种不同浓度。我们鉴定了一组药物，包括硼替佐米、17-AAG、洋地黄毒苷、星形孢菌素、地高辛、卢比替康和曲美曲沙，它们抑制脉络膜细胞生长，在U-CH 1细胞中的效力为10至370 nM，但在U-CH 2细胞中的效力较低。这些药物中的大多数还诱导半胱天冬酶3/7活性，其等级顺序与对U-CH 1细胞的细胞毒性作用相似。斑蝥素、地高辛、洋地黄毒苷、星形孢菌素和硼替佐米对细胞系和3种原代培养的脉络膜细胞显示出相似的抑制作用。硼替佐米与拓扑异构酶I和II抑制剂的联合治疗增加了U-CH 2和患者来源的原代培养物中的治疗效力。我们的研究结果提供了有用的信息，重新利用目前批准的药物治疗脉络膜和潜在的联合治疗方法。
Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.
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影响因子：
4.1
作者：
Huang, Ruili;Southall, Noel;Austin, Christopher P.
通讯作者：
Austin, Christopher P.
影响因子：
3.7
作者：
Scheil, S;Brüderlein, S;Möller, P
通讯作者：
Möller, P
影响因子：
5.8
作者：
Miller, Susanne C.;Huang, Ruili;Sakamuru, Srilatha;Shukla, Sunita J.;Attene-Ramos, Matias S.;Shinn, Paul;Van Leer, Danielle;Leister, William;Austin, Christopher P.;Xia, Menghang
通讯作者：
Xia, Menghang
影响因子：
3
作者：
Falchook, G. S.;Duvic, M.;Kurzrock, R.
通讯作者：
Kurzrock, R.
影响因子：
10.4
作者：
Xia M;Huang R;Witt KL;Southall N;Fostel J;Cho MH;Jadhav A;Smith CS;Inglese J;Portier CJ;Tice RR;Austin CP
通讯作者：
Austin CP