2. Academic Validation
  3. H2O2/Peroxynitrite-Activated Hydroxamic Acid HDAC Inhibitor Prodrugs Show Antileukemic Activities against AML Cells

H2O2/Peroxynitrite-Activated Hydroxamic Acid HDAC Inhibitor Prodrugs Show Antileukemic Activities against AML Cells

  • ACS Med Chem Lett. 2018 Jun 13;9(7):635-640. doi: 10.1021/acsmedchemlett.8b00057.
Yi Liao 1,  Liping Xu 1,  Siyu Ou 1,  Holly Edwards 2,  Daniel Luedtke 2 3,  Yubin Ge 2,  Zhihui Qin 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48201, United States.
  • 2 Department of Oncology and the Molecular Therapeutics Program of the Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan 48201, United States.
  • 3 Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, Michigan 48201, United States.
PMID: 30034592 DOI: 10.1021/acsmedchemlett.8b00057
Abstract

Occurrence of acute myeloid leukemia (AML) results in abundant endogenous Reactive Oxygen Species (ROS)/reactive nitrogen species (RNS) in AML cells and in disease-relevant microenvironments. Histone deacetylase inhibitor (HDACi) prodrug approach was designed accordingly by masking the hydroxamic acid zinc binding group with hydrogen peroxide (H2O2)/peroxynitrite (PNT)-sensitive, self-immolative aryl boronic acid moiety. Model prodrugs 5-82 and 5-23 were activated in AML cells to release cytotoxic HDACis, evidenced by inducing acetylation markers and reducing viability of AML cells. Intracellular activation and antileukemic activities of prodrug were increased or decreased by ROS/PNT inducers and scavengers, respectively. Prodrugs 5-82 and 5-23 also enhanced the potency of chemotherapy drug cytarabine, supporting the potentials of this prodrug class in combinatorial treatment.

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