Enhancement of arabinocytosine (AraC) toxicity to AML cells by a differentiation agent combination

Xuening Wang, Jonathan S. Harrison, George P. Studzinski

Research output: Contribution to journalReview articlepeer-review

15 Scopus citations

Abstract

Arabinocytosine (AraC, also known as cytarabine) is one of the mainstays of AML therapy, but like other DNA damaging therapeutic agents it is rarely curative by itself. There is an emerging realization that the therapeutic outcomes may be improved by combining AraC with other compounds. Here we report that the addition of a differentiating agent combination immediately following AraC damage to AML blasts, selectively increases the cell kill. The experiments were performed using cultured cells from established cell lines of AML (HL60 and U937). The cells were exposed to 100 nM AraC, a concentration which produced approximately 25–50% cell kill, followed by a combination of 100 nM 1alpha-hydroxyvitamin D2 (1-D2) and 10 μM carnosic acid (CA), which together can serve as a powerful differentiating agent combination for AML cells, but are not toxic alone. AraC-induced cell death, measured by annexin V/propidium iodide, was significantly (p < 0.01) increased by the 1-D2/CA combination in both cell lines, but not by 1-D2 or CA alone. The enhancement of cell death occurred by both apoptosis and necrosis, was associated with increased DNA damage and with higher levels of DNA damage response (DDR) activated marker Chk1, but the expression of p27, a cell cycle inhibitor protein, was not enhanced by 1-D2/CA. The principal finding is that a vitamin D analog 1-D2 combined with a plant-derived antioxidant CA can markedly augment the cytotoxic action of AraC, an anti-leukemia therapeutic agent.

Original languageEnglish (US)
Pages (from-to)72-78
Number of pages7
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume164
DOIs
StatePublished - Nov 1 2016

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Keywords

  • Acute myeloid leukemia (AML)
  • Apoptosis
  • AraC
  • Chk1
  • Plant antioxidant
  • VDR
  • Vitamin D analog

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