In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 399-399
Abstract:
Myelodysplastic syndrome (MDS) is a clonal disorder of the hematopoietic cells occurring in elderly patients in a majority of instances. They are defined by ineffective hematopoiesis with peripheral blood cytopenias and by the risk of evolution to acute myeloid leukemia (AML). Hypomethylating agents (HMA), 5-azacytidine (AZA) and 2-deoxy-5-azacytidine (DAC), have demonstrated clinical activities with cytologic and cytogenetic responses in patients with MDS, but potential problems of both agents include the development of intrinsic and acquired resistance. HMA-resistant patients have very poor prognosis, and this cohort of patients constitutes an important area of research. To understand mechanisms of HMA-resistance and overcome the resistance, we tried to establish HMA-resistant cells using MOLM-13, which is a cell line from a patient with AML evolved from MDS. Original MOLM-13 cell line was sensitive to both AZA and DAC in vitro. MOLM-13 cells were exposed continuously to increasing concetrations of AZA or DAC and we could establish an AZA-resistant cell line (MOLM/AZA-1) and a DAC-resistant cell line (MOLM/DAC-5). The IC50 of AZA in MOLM/AZA-1 was 96.26 µM compared to 0.11 µM of the parent cell line; 800-fold increase in resistance to AZA. The IC50 of DAC in MOLM/DAC-5 was 207.7 µM compared to 0.07 µM of the parent cell line; 2000-fold increase in resistance to DAC. We treated th AZA- and DAC-resistant cells with vorinostat (SAHA) and a novel agent, CG200745 to test whether the histone deacetylase (HDAC) inhibitors could overcome the HMA-resistance. Cell viability assays showed that HMA-resistant cells were sensitive to both HDAC inhibitors, which dramatically decreased anti-apoptotic proteins (XIAP, MCL-1 and BCL-2) and increased PARP cleavages in the HMA-resistant cell lines. In conclusion, we successfully established established AZA- and DAC-resistant cell lines from an AML/MDS cell line, MOLM-13, and found that HDAC inhibitors might be promising in overcoming HMA-resistance. Further studies with the HMA-resistant cell lines are ongoing for elucidation of resistance mechanisms and possible role of other novel agents to overcome the HMA-resistance. Citation Format: Dae Ro Choi, Eun-Hye Hur, Ju Hyun Moon, Bon-Kwan Goo, Yunsuk Choi, Do Young Lee, Seonggu Ro, Joong Myung Cho, Je-Hwan Lee. Establishment of hypomethylating agent-resistant cell lines using a cell line from a patient with acute myeloid leukemia evolved from myelodysplastic syndrome (MOLM-13). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 399. doi:10.1158/1538-7445.AM2014-399
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-399
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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