Four clinically utilized drugs were identified and validated for treatment of adrenocortical cancer using quantitative h
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RESEARCH
Open Access
Four clinically utilized drugs were identified and validated for treatment of adrenocortical cancer using quantitative high-throughput screening Naris Nilubol1*, Lisa Zhang1, Min Shen2, Ya-Qin Zhang2, Mei He1, Christopher P Austin2 and Electron Kebebew1
Abstract 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 2. 3) Z-factor which is a measure of statistical effect size as described by Zhang et al [16]. In brief, Z = 1 is an ideal assay where no variation (standard deviation = 0) or dynamic range is infinite, Z between 0.5 and 1.0 is an excellent assay, Z between 0 and 0.5 is a marginal assay, and Z < 0 is not a useful assay. We selected the candidate compounds that demonstrated antiproliferative efficacy of > 60% and IC50 < 1 μM for further validation. Compounds that meet our criteria are likely to have antineoplastic activity against ACC at clinically achievable serum level. We then analyzed the characteristics of these drugs, including the current available preparation and route of administration, maximum serum concentrations after systemic delivery, and drug half-life in humans (Table 1). We selected 4 active drugs that could be administered orally or intravenously with IC50 equal to or below maximal serum concentration for validation. To further assess the drug categories that were active against NCI-H295R, we performed enrichment analysis by therapeutic category. The enrichment score is the ratio of number of active drugs to the total of numbers of tested drugs in the same therapeutic category.
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We explored the use of qHTS as a tool to screen for compounds with antiproliferative activity in normal cells or in other cancer cells by assessing the activities of active drugs in the following normal and cancer cell lines: TPC-1: papillary thyroid cancer cell line, NF-kB: ME180 human cervical carcinoma cell line, MRC5: normal human fetal lung fibroblasts, Mesangial: human kidney glomerular mesangial cell line, LAM: lymphoangioleiomyosis cell line (LAM, a rare lung disease that results in a proliferation of disorderly smooth muscle growth) (Figure 2B). In vitro validation of qHTS assay
1. Cell proliferation assay The candidate drugs with antiproliferative activity were v
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