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

Journal of Translational Medicine

Research

Lisa Zhang¹  Naris Nilubol¹  Mei He¹  Electron Kebebew¹  Min Shen²  Ya-Qin Zhang²  Christopher P Austin² 

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

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

DOI  :  10.1186/1479-5876-10-198

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

来源: Springer

【 摘 要 】

BackgroundDrug 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.MethodsA 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.ResultsWe 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.ConclusionsqHTS 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】

CC BY   
© Nilubol et al.; licensee BioMed Central Ltd. 2012