We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Synergistic Interactions between the Hypomethylating Agent Thio-Deoxycytidine and Venetoclax in Myelodysplastic Syndrome Cells.
- Authors
Xiaoyan Hu; Lin Li; Nkwocha, Jewel; Sharma, Kanika; Liang Zhou; Grant, Steven
- Abstract
Interactions between the novel hypomethylating agent (HMA) thio-deoxycytidine (T-dCyd) and the BCL-2 antagonist ABT-199 (venetoclax) have been examined in human myelodysplastic syndrome (MDS) cells. The cells were exposed to agents alone or in combination, after which apoptosis was assessed, and a Western blot analysis was performed. Co-administration of T-dCyd and ABT-199 was associated with the down-regulation of DNA methyltransferase 1 (DNMT1) and synergistic interactions documented by a Median Dose Effect analysis in multiple MDS-derived lines (e.g., MOLM-13, SKM-1, and F-36P). Inducible BCL-2 knock-down significantly increased T-dCyd’s lethality in MOLM-13 cells. Similar interactions were observed in the primary MDS cells, but not in the normal cord blood CD34+ cells. Enhanced killing by the T-dCyd/ABT-199 regimen was associated with increased reactive oxygen species (ROS) generation and the down-regulation of the anti-oxidant proteins Nrf2 and HO-1, as well as BCL-2. Moreover, ROS scavengers (e.g., NAC) reduced lethality. Collectively, these data suggest that combining T-dCyd with ABT-199 kills MDS cells through an ROS-dependent mechanism, and we argue that this strategy warrants consideration in MDS therapy.
- Subjects
MYELODYSPLASTIC syndromes; WESTERN immunoblotting; VENETOCLAX; REACTIVE oxygen species; SEROTONIN syndrome; CORD blood
- Publication
Hematology Reports, 2023, Vol 15, Issue 1, p91
- ISSN
2038-8322
- Publication type
Article
- DOI
10.3390/hematolrep15010010