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

• Published in: Journal of cellular physiology Vol. 235; no. 1; pp. 573 - 586
• Main Authors: Wang, Xuening, Dawod, Alaa, Nachliely, Matan, Harrison, Jonathan S., Danilenko, Michael, Studzinski, George P.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.01.2020
• Subjects: Acetylcysteine; Acute myeloid leukemia; Antioxidants; Apoptosis; Calciferol; carnosic acid; Cell death; Cell differentiation; Change detection; Cytotoxicity; Differentiation (biology); Leukemia; Mortality; Myeloid leukemia; N‐acetyl cysteine; Reactive oxygen species; ROS; Therapy; Vitamin D; vitamin D receptor; Vitamin D receptors; N-acetyl cysteine; vitamin D receptor; acute myeloid leukemia; cell death; carnosic acid; ROS
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.28996

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. The diagram shows that the exposure of acute myeloid leukemia cells to arabinocytosine (AraC) produces intracellular reactive oxygen species (ROS), which cause DNA damage and are major contributors to cell death. We now show that, while enhancing AraC‐induced cell death, differentiation agents (doxercalciferol/carnosic acid [D2/CA]) diminish ROS abundance. Vitamin D receptor (VDR)‐dependent cell death is signaled by an ASK1‐regulated pathway. N‐acetyl cysteine (NAC) reduces this enhancement primarily by inhibiting the enhancing effect of D2/CA on VDR expression. Although additional actions of NAC on cell death signaling are not excluded, these do not include changes in the cellular levels of ROS.