title: Selective AKR1C3 Inhibitors Potentiate Chemotherapeutic Activity in Multiple Acute Myeloid Leukemia (AML) Cell Lines.
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.
authors: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy , Amarillo, Texas 79106, United States.
authors: Kshitij
authors: K
authors: Verma
authors: Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6160, United States.
authors: Tianzhu
authors: T
authors: Zang
authors: Department of Biomedical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy , Amarillo, Texas 79106, United States.
authors: Nehal
authors: N
authors: Gupta
authors: Center of Excellence in Environmental Toxicology, Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania 19104-6160, United States.
authors: Trevor M
authors: TM
authors: Penning
authors: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, Texas 79106, United States; Center for Chemical Biology, Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409-1061, United States.
authors: Paul C
authors: PC
authors: Trippier
keywords: AKR1C3 Inhibitor; acute myeloid leukemia; adjuvant; daunorubicin; etoposide; synergism