Four clinically utilized drugs were identified and validated for treatment of adrenocortical cancer using quantitative high-throughput screening

Journal of Translational Medicine

Electron Kebebew²  Christopher P Austin¹  Mei He²  Ya-Qin Zhang¹  Min Shen¹  Lisa Zhang²  Naris Nilubol² 

[1] National Center for Advancing Translational Sciences, NIH Chemical Genomics Center, NIH, Bethesda, MD, USA;Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Rm. 3-3940, 10 Center Drive, MSC 1201, Bethesda, MD, 20892, USA

关键词: Indication switching;    Drug repurposing;    Chemotherapy;    High throughput drug screening;    Adrenocortical cancer;   

Others  :  829420
DOI  :  10.1186/1479-5876-10-198

 received in 2012-04-17, accepted in 2012-08-11,  发布年份 2012

【 摘 要 】

Background

Drug repurposing for cancer treatment is an emerging approach to discover clinically approved drugs that demonstrate antineoplastic effect. The effective therapeutics for patients with advanced adrenocortical carcinoma(ACC) are greatly needed. The objective of this study was to identify and validate drugs with antineoplastic effect in ACC cells using a novel quantitative high-throughput drug screening (qHTS) technique.

Methods

A quantitative high-throughput proliferation assay of 2,816 clinically approved drugs was performed in the NCI-H295R ACC cell line. We validated the antiproliferative effect of candidate compounds in NCI-H295R cells. Further validation was performed in 3-dimensional multicellular aggregates (MCA) of NCI-H295R and SW-13 cell lines.

Results

We identified 79 active compounds against ACC cells; 21 had an efficacy ≥60% and IC₅₀ <1 μM. The top drug categories enriched were cardiotonic, antiseptic, and antineoplastic. We selected Bortezomib, ouabain, Methotrexate, pyrimethamine for validation. All had an antiproliferative effect in monolayer culture of NCI-H295R cells at clinical achievable serum level. Bortezomib and ouabain inhibited growth of MCA in both cell lines at a low concentration (10 fold below IC₅₀). Methotrexate inhibited growth and caused disintegration of MCA in both cell lines at concentrations well below the maximum serum level (10 to 100 fold of IC₅₀). Pyrimethamine caused growth inhibition in both cell lines at 10 fold of IC₅₀ concentration.

Conclusions

qHTS of previously approved compounds is an effective and efficient method to identify anticancer drugs for a rare cancer such as ACC. We have validated the antineoplastic effect of Bortezomib, ouabain, Methotrexate and pyrimethamine, which could be translated into clinical trials in patients with locally advanced and/or metastatic ACC.

【 授权许可】

   
2012 Nilubol et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

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