Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia

Katja Karjalainen, Renata Pasqualini, Jorge E. Cortes, Steven M. Kornblau, Benjamin Lichtiger, Susan O'Brien, Hagop M. Kantarjian, Richard L. Sidman, Wadih Arap, Erkki Koivunen

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

BACKGROUND The authors developed an ex vivo methodology to perform drug library screening against human leukemia. METHODS The strategy for this screening relied on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. Several advantages were observed: 1) partial recapitulation of the leukemia microenvironment, 2) use of native hemoglobin oxygenation as a real-time sensor/reporter, 3) cost-effectiveness, 4) species specificity, and 5) a format that enables high-throughput screening. RESULTS For a proof of concept, a chemical library (size, approximately 20,000 compounds) was screened against human leukemia cells. Seventy compounds were identified ("hit" rate, 0.35%; Z-factor = 0.71) that had activity, and 20 compounds were examined to identify 18 true-positive compounds (90%). Finally, the results demonstrated that carbonohydraxonic diamide group-containing compounds are potent antileukemia agents that induce cell death in leukemia cells and in patient-derived samples. CONCLUSIONS The current results indicated that this unique functional assay can identify novel drug candidates and can help with the development of future applications in personalized drug selection for patients with leukemia. Cancer 2014;120:589-602.

Original languageEnglish (US)
Pages (from-to)589-602
Number of pages14
JournalCancer
Volume120
Issue number4
DOIs
StatePublished - Feb 15 2014
Externally publishedYes

Keywords

  • blood
  • bone marrow
  • chemical library
  • drug screening
  • hypoxia
  • leukemia targeting
  • tumor microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Karjalainen, K., Pasqualini, R., Cortes, J. E., Kornblau, S. M., Lichtiger, B., O'Brien, S., Kantarjian, H. M., Sidman, R. L., Arap, W., & Koivunen, E. (2014). Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia. Cancer, 120(4), 589-602. https://doi.org/10.1002/cncr.28419