Abstract
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.
Highlights
Drug repurposing for cancer treatment is an emerging approach to discover clinically approved drugs that demonstrate antineoplastic effect
Quantitative high throughput screening of clinical drug library Overall performance of quantitative high-throughput drug screening (qHTS) was excellent with low variation, high signal to background (S/B) ratio and Z-factor between 0.5 to 1
When compared to other cancer types, a distinct activity pattern was observed for NCIH295R cells, in which several of the drugs were active against other cancer cells, but they usually showed less activity or even no antiproliferative effect in cervical cancer cells (NF-kB) (Figure 2B)
Summary
Drug repurposing for cancer treatment is an emerging approach to discover clinically approved drugs that demonstrate antineoplastic effect. Some drugs found to have an anticancer effect may reduce the risk of developing cancer and could be used for prevention of common cancers in high risk individuals [8,9,10,11]. Given these inherent advantages of drug repurposing and the lack of effective therapy for ACC, we performed quantitative high throughput screening (qHTS) of 2,816 clinical approved drugs in the NCI-H295R ACC cell line. We validated a select number of drugs in 3-dimensional multicellular aggregates (MCA) of NCI-H295R and SW-13 ACC cell lines
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