Synergism between arsenic trioxide and heat shock protein 90 inhibitors on signal transducer and activator of transcription protein 3 activity--pharmacodynamic drug-drug interaction modeling.
OBJECTIVE
Constitutive signal transducer and activator of transcription 3 (STAT3) activity, observed in approximately 50% of acute myelogenous leukemia cases and associated with adverse treatment outcome, is down-regulated by arsenic trioxide (ATO). Heat shock protein (HSP) 90 is a molecular chaperone involved in signal transduction pathways. We hypothesized that HSP90 inhibitors will potentiate ATO effect on constitutive STAT3 activity and cell killing. One concern was that the effect of ATO and HSP90 inhibitors will result in up-regulation of HSP70, a protein known to inhibit apoptosis.


METHODS
We have used a semimechanistic pharmacodynamic model to characterize concentration-effect relationships of ATO and HSP90 inhibitors on constitutive STAT3 activity, HSP70 expression, and cell death in a cell line model.


RESULTS
Pharmacodynamic interaction of ATO and three HSP90 inhibitors showed synergistic interactions in inhibiting constitutive STAT3 activity and inducing cell death, in spite of a concurrent synergistic up-regulation of HSP70.


CONCLUSIONS
These preliminary results provide a basis for studying the combined role of ATO with HSP90 inhibitors in acute myelogenous leukemia with constitutive STAT3 activity.
Wetzler
Meir
M
Roswell Park Cancer Institute and State University of New York at Buffalo, Buffalo, New York 14263, USA. meir.wetzler@roswellpark.org
Earp
Justin C
JC
Brady
Michael T
MT
Keng
Michael K
MK
Jusko
William J
WJ
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004357:Drug Synergism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008962:Models, Theoretical; D010087:Oxides / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000187:drug effects*
D000970:Antineoplastic Agents; D001152:Arsenicals; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D010087:Oxides; D050796:STAT3 Transcription Factor; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; C112765:tanespimycin; D000077237:Arsenic Trioxide; C001277:geldanamycin