Differentiation agents increase the potential AraC therapy of AML by reactivating cell death pathways without enhancing ROS generation |
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| Authors: | Xuening Wang Alaa Dawod Matan Nachliely Jonathan S. Harrison Michael Danilenko George P. Studzinski |
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| Affiliation: | 1. Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, State University of New Jersey, Newark, New Jersey;2. Department of Clinical Biochemistry & Pharmacology, Ben-Gurion University of the Negev, Be'er Sheva, Israel;3. Division of Hematology and Oncology, University of Connecticut School of Medicine, Farmington, Connecticut |
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| 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. |
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| Keywords: | acute myeloid leukemia carnosic acid cell death N-acetyl cysteine ROS vitamin D receptor |
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