Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines

Kshitij Verma, Tianzhu Zang, Nehal Gupta, Trevor M. Penning, Paul C. Trippier

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

We report the design, synthesis, and evaluation of potent and selective inhibitors of aldo-keto reductase 1C3 (AKR1C3), an important enzyme in the regulatory pathway controlling proliferation, differentiation, and apoptosis in myeloid cells. Combination treatment with the nontoxic AKR1C3 inhibitors and etoposide or daunorubicin in acute myeloid leukemia cell lines, elicits a potent adjuvant effect, potentiating the cytotoxicity of etoposide by up to 6.25-fold and the cytotoxicity of daunorubicin by >10-fold. The results validate AKR1C3 inhibition as a common adjuvant target across multiple AML subtypes. These compounds in coadministration with chemotherapeutics in clinical use enhance therapeutic index and may avail chemotherapy as a treatment option to the pediatric and geriatric population currently unable to tolerate the side effects of cancer drug regimens.

Original languageEnglish (US)
Pages (from-to)774-779
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume7
Issue number8
DOIs
StatePublished - Aug 11 2016

Keywords

  • AKR1C3 Inhibitor
  • acute myeloid leukemia
  • adjuvant
  • daunorubicin
  • etoposide
  • synergism

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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