TY - JOUR
T1 - Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine
AU - Mesa, Ruben A.
AU - Loegering, David
AU - Powell, Heather L.
AU - Flatten, Karen
AU - Arlander, Sonnet J.H.
AU - Dai, Nga T.
AU - Heldebrant, Michael P.
AU - Vroman, Benjamin T.
AU - Smith, B. Douglas
AU - Karp, Judith E.
AU - Ten Eyck, Cynthia J.
AU - Erlichman, Charles
AU - Kaufmann, Scott H.
AU - Karnitz, Larry M.
PY - 2005/7/1
Y1 - 2005/7/1
N2 - Previous studies demonstrated that ataxia telangiectasia mutated- and Rad3-related (ATR) kinase and its downstream target checkpoint kinase 1 (Chk1) facilitate survival of cells treated with nucleoside analogs and other replication inhibitors. Recent results also demonstrated that Chk1 is depleted when cells are treated with heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The present study examined the effects of 17-AAG and its major metabolite, 17-aminogeldanamycin (17-AG), on Chk1 levels and cellular responses to cytarabine in human acute myelogenous leukemia (AML) cell lines and clinical isolates. Cytarabine, at concentrations as low as 30 nM, caused activating phosphorylation of Chk1, loss of the phosphatase Cdc25A, and S-phase slowing. Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis. Additional studies demonstrated that small inhibitory RNA (SiRNA) depletion of Chk1 also sensitized cells to cytarabine, whereas disruption of the phosphatidytinositol 3-kinase (PI3k) signaling pathway, which is also blocked by Hsp90 inhibition, did not. Collectively, these results suggest that treatment with 17-AAG might represent a means of reversing checkpoint-mediated cytarabine resistance in AML.
AB - Previous studies demonstrated that ataxia telangiectasia mutated- and Rad3-related (ATR) kinase and its downstream target checkpoint kinase 1 (Chk1) facilitate survival of cells treated with nucleoside analogs and other replication inhibitors. Recent results also demonstrated that Chk1 is depleted when cells are treated with heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The present study examined the effects of 17-AAG and its major metabolite, 17-aminogeldanamycin (17-AG), on Chk1 levels and cellular responses to cytarabine in human acute myelogenous leukemia (AML) cell lines and clinical isolates. Cytarabine, at concentrations as low as 30 nM, caused activating phosphorylation of Chk1, loss of the phosphatase Cdc25A, and S-phase slowing. Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis. Additional studies demonstrated that small inhibitory RNA (SiRNA) depletion of Chk1 also sensitized cells to cytarabine, whereas disruption of the phosphatidytinositol 3-kinase (PI3k) signaling pathway, which is also blocked by Hsp90 inhibition, did not. Collectively, these results suggest that treatment with 17-AAG might represent a means of reversing checkpoint-mediated cytarabine resistance in AML.
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U2 - 10.1182/blood-2004-09-3523
DO - 10.1182/blood-2004-09-3523
M3 - Article
C2 - 15784732
AN - SCOPUS:22044437522
SN - 0006-4971
VL - 106
SP - 318
EP - 327
JO - Blood
JF - Blood
IS - 1
ER -