Differentiation agents increase the potential AraC therapy of AML by reactivating cell death pathways without enhancing ROS generation

Xuening Wang, Alaa Dawod, Matan Nachliely, Jonathan S. Harrison, Michael Danilenko

Research output: Contribution to journalArticle

Abstract

Acute myeloid leukemia (AML) has a poor prognosis and requires new approaches for treatment. We have reported that a combination of vitamin D-based cell differentiation agents (doxercalciferol/carnosic acid [D2/CA]) added following the cytotoxic drug arabinocytosine (AraC) increases AML cell death (CD), a model for improved therapy of this disease. Because AraC-induced CD is known to involve reactive oxygen species (ROS) generation, here we investigated if the modulation of cellular REDOX status plays a role in the enhancement of cell death (ECD) by D2/CA. Using thiol antioxidants, such as N-acetyl cysteine (NAC), we found a significant inhibition of ECD, yet this occurred in the absence of any detectable change in cellular ROS levels. In contrast, NAC reduced the vitamin D receptor (VDR) abundance and its signaling of ECD. Importantly, VDR knockdown and NAC similarly inhibited ECD without producing an additive effect. Thus, the proposed post-AraC therapy may be compromised by agents that reduce VDR levels in AML blasts.

Original languageEnglish (US)
Pages (from-to)573-586
Number of pages14
JournalJournal of Cellular Physiology
Volume235
Issue number1
DOIs
StatePublished - Jan 1 2020

Fingerprint

Cell death
Acute Myeloid Leukemia
Reactive Oxygen Species
Cell Death
Acetylcysteine
Calcitriol Receptors
Cysteine
Therapeutics
Myeloid Cells
Sulfhydryl Compounds
Vitamin D
Cell Differentiation
Antioxidants
Modulation
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Keywords

  • acute myeloid leukemia
  • carnosic acid
  • cell death
  • N-acetyl cysteine
  • ROS
  • vitamin D receptor

Cite this

Wang, Xuening ; Dawod, Alaa ; Nachliely, Matan ; Harrison, Jonathan S. ; Danilenko, Michael. / Differentiation agents increase the potential AraC therapy of AML by reactivating cell death pathways without enhancing ROS generation. In: Journal of Cellular Physiology. 2020 ; Vol. 235, No. 1. pp. 573-586.
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Differentiation agents increase the potential AraC therapy of AML by reactivating cell death pathways without enhancing ROS generation. / Wang, Xuening; Dawod, Alaa; Nachliely, Matan; Harrison, Jonathan S.; Danilenko, Michael.

In: Journal of Cellular Physiology, Vol. 235, No. 1, 01.01.2020, p. 573-586.

Research output: Contribution to journalArticle

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