Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2004-14 |
| Number of pages | 11 |
| Journal | Leukemia & Lymphoma |
| Volume | 53 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 2012 |
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DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells. / Dinis, Joana; Silva, Vânia; Gromicho, Marta ; Martins, Célia ; Laires, António ; Tavares, P; Rendeiro, Paula; Torres, Fátima ; Rueff, J.; Rodrigues, AS.
In: Leukemia & Lymphoma, Vol. 53, No. 10, 2012, p. 2004-14.Research output: Contribution to journal › Article
TY - JOUR
T1 - DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells.
AU - Dinis, Joana
AU - Silva, Vânia
AU - Gromicho, Marta
AU - Martins, Célia
AU - Laires, António
AU - Tavares, P
AU - Rendeiro, Paula
AU - Torres, Fátima
AU - Rueff, J.
AU - Rodrigues, AS
N1 - WOS:000308213400013
PY - 2012
Y1 - 2012
N2 - Abstract Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.
AB - Abstract Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H(2)O(2) and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H(2)O(2) and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.
KW - EXPRESSION
KW - MBD4
KW - MED1
KW - DNA repair
KW - MESYLATE
KW - PROTEIN-4
KW - Chronic myeloid leukemia
KW - oxidative damage
KW - INTEGRITY
KW - GLYCOSYLASE
KW - genotoxicity
KW - BASE EXCISION-REPAIR
KW - resistance to imatinib
KW - CHRONIC MYELOGENOUS LEUKEMIA
KW - MECHANISMS
U2 - 10.3109/10428194.2012.681654
DO - 10.3109/10428194.2012.681654
M3 - Article
VL - 53
SP - 2004
EP - 2014
JO - Leukemia & Lymphoma
JF - Leukemia & Lymphoma
SN - 1042-8194
IS - 10
ER -