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Updated: May 18, 2026
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
Four clinically utilized drugs were identified and validated for treatment of adrenocortical cancer using
Naris Nilubol1, Lisa Zhang, Min Shen
1Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, 10 Center Drive, MSC 1201, Bethesda, MD 20892, USA. niluboln@mail.nih.gov
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.
Insights
Drug repurposing identified Bortezomib, ouabain, Methotrexate, and pyrimethamine as potential treatments for adrenocortical carcinoma (ACC). These compounds show antiproliferative effects in ACC cells, offering new therapeutic avenues for this rare cancer.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- Drug repurposing offers a promising strategy for identifying novel cancer therapeutics.
- Adrenocortical carcinoma (ACC) presents a significant unmet need for effective treatments.
- Quantitative high-throughput drug screening (qHTS) enables efficient discovery of antineoplastic agents.
Purpose of the Study:
- To identify and validate existing drugs with antineoplastic effects against ACC cells.
- To leverage qHTS for rapid screening of a large drug library.
- To assess the efficacy of candidate drugs in relevant ACC cell models.
Main Methods:
- A qHTS proliferation assay was conducted on 2,816 clinically approved drugs using the NCI-H295R ACC cell line.
- Candidate compounds were validated for antiproliferative activity in NCI-H295R cells.
- Further validation involved testing in 3D multicellular aggregates (MCA) of NCI-H295R and SW-13 cell lines.
Main Results:
- 79 active compounds were identified against ACC cells, with 21 showing efficacy ≥ 60% and IC50 <1 μM.
- Top drug categories included cardiotonic, antiseptic, and antineoplastic agents.
- Bortezomib, ouabain, Methotrexate, and pyrimethamine demonstrated significant antiproliferative effects in both monolayer and 3D MCA models at clinically relevant concentrations.
Conclusions:
- qHTS of approved compounds is an effective method for discovering anticancer drugs for rare cancers like ACC.
- Bortezomib, ouabain, Methotrexate, and pyrimethamine show validated antineoplastic effects in ACC.
- These findings support the translation of these drugs into clinical trials for advanced ACC patients.
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