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

Wetzler, Meir; Earp, Justin; Brady, Michael T.; Keng, Michael; Jusko, William J.

doi:10.1158/1078-0432.ccr-06-2468

Cited by 17 publications

(21 citation statements)

References 24 publications

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“…Previous studies demonstrated that sodium arsenite inhibits interleukin-6-dependent tyrosine phosphorylation of STAT3 in HepG2 cells via direct suppression of the tyrosine kinase JAK1 (41). Other studies have shown that As 2 O 3 suppresses activation of STAT1, STAT3, and STAT5 in AML cells and inhibits activation of JAK1 and JAK2, which phosphorylate STATs (42), whereas there is also evidence for a synergism between As 2 O 3 and Hsp90 inhibitors in STAT3 activity (43).…”

Section: Mechanisms Of Arsenic-induced Cell Deathmentioning

confidence: 99%

Biological Responses to Arsenic Compounds

Platanias

2009

Journal of Biological Chemistry

141

127

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Arsenic is a metalloid that generates various biological effects on cells and tissues. Depending on the specific tissue exposed and the time and degree of exposure, diverse responses can be observed. In humans, prolonged and/or high dose exposure to arsenic can have a variety of outcomes, including the development of malignancies, severe gastrointestinal toxicities, diabetes, cardiac arrhythmias, and death. On the other hand, one arsenic derivative, arsenic trioxide (As 2 O 3 ), has important antitumor properties. This agent is a potent inducer of antileukemic responses, and it is now approved by the Food and Drug Administration for the treatment of acute promyelocytic leukemia in humans. The promise and therapeutic potential of arsenic and its various derivatives have been exploited for hundreds of years. Remarkably, research focused on the potential use of arsenic compounds in the treatment of human diseases remains highly promising, and it is an area of active investigation. An emerging approach of interest and therapeutic potential involves efforts to target and block cellular pathways activated in a negative feedback manner during treatment of cells with As 2 O 3 . Such an approach may ultimately provide the means to selectively enhance the suppressive effects of this agent on malignant cells and render normally resistant tumors sensitive to its antineoplastic properties.

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Section: Mechanisms Of Arsenic-induced Cell Deathmentioning

confidence: 99%

Biological Responses to Arsenic Compounds

Platanias

2009

Journal of Biological Chemistry

141

127

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“…We have shown that arsenic trioxide (ATO) down-regulates constitutive STAT3 activity in AML cells within 6 h, without affecting cell survival until 48 h [2]. Since heat shock protein (HSP) 90 is implicated in maintaining the conformation, stability and function of key proteins involved in signal transduction pathways, we demonstrated that the different HSP90 inhibitors [geldanamycin, 17-allylamino-17-demethoxygeldanamycin (17-AAG), and 17-(dimethyl-aminoethylamino)-17-demethoxygeldanamycin (NSC 707545, 17-DMAG)] augment ATO’s down-regulating effect on constitutive STAT3 (P-STAT3) [3]. Since 17-AAG has poor solubility, the water soluble derivative, 17-DMAG, which is more biologically available, was tested in the current study.…”

Section: Introductionmentioning

confidence: 99%

“…The interaction model is not limited to mass-law drug–receptor binding equations, but provides estimates of how much each drug contributes to the interaction after binding to their respective targets. These models were designed to study the effect(s) of down-regulating HSP70 on the known synergistic effect of ATO and 17-DMAG on constitutive STAT3 activity [3]. We therefore incorporated data from our previous study [3] into the current model.…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of heat shock protein 70 improves arsenic trioxide and 17-DMAG effects on constitutive signal transducer and activator of transcription 3 activity

Ghoshal

Rao

Earp

et al. 2009

Cancer Chemother Pharmacol

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Purpose Signal transducer and activator of transcription 3 (STAT3) has been shown to be constitutively active in approximately 50% of patients with acute myeloid leukemia and is associated with worse outcome. Arsenic trioxide (ATO) synergizes with the heat shock protein (HSP) 90 inhibitor, 17-DMAG, to down-regulate STAT3 activity. However, both agents up-regulate HSP70, an anti-apoptotic protein. We therefore examined whether down-regulating HSP70 with short interference (si) RNA will affect ATO and 17-DMAG effects on constitutive STAT3 activity. Experimental design A semi-mechanistic pharmacodynamic model was used to characterize concentration–effect relationships of ATO and 17-DMAG effects on constitutive STAT3 activity and HSP70 expression with or without siRNA against HSP70 in a cell line model. Results Treatment with siRNA for HSP70 resulted in a stronger degree of synergism on down-regulation of STAT3 activity by ATO and 17-DMAG. However, treatment with siRNA for HSP70 resulted in less synergism on up-regulation of HSP70 by the two drugs. Conclusions Down-regulation of HSP70 improves ATO and 17-DMAG effects on constitutive STAT3 activity. These results further provide a basis for studying the combined role of ATO with a HSP90 inhibitor such as 17-DMAG in AML with constitutive STAT3 activity.

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“…Arsenite can induce HSPs expression in a variety of cells 14,15 . HSPs are molecular chaperones which help protein folding and transportation 16,17 .…”

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confidence: 99%

Abrogating HSP Response Augments Cell Death Induced by As2O3 in Glioma Cell Lines

Song

Chen²,

Wu³

2010

Can. j. neurol. sci.

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504Malignant gliomas are the most common and lethal tumors of the central nervous system and are resistant to many kinds of treatment, including radiation, chemotherapy, and other adjuvant therapies 1,2 . Although considerable progress has been made in the treatment of glioma, its prognosis is still very poor 3 . The inefficacy of these therapeutic modalities in curing gliomas is due to the resistance of glioma cells and the difficulty of achieving complete tumor resection. There is therefore an urgent need to devise alternative therapeutic strategies to combat gliomas.We previously reported that Arsenic Trioxide (As2O3, or ATO) can inhibit glioma growth both in vitro and in vivo [4][5][6] , which demonstrated the potent therapeutic effects of this drug. ABSTRACT: Objectives:We previously reported that Arsenic trioxide (ATO) can inhibit glioma growth both in vitro and in vivo. While the use of ATO alone for solid tumor treatment sometimes was found to be ineffective which may be due to the protective pathways including heat shock proteins (HSPs) response induced by ATO. In this study, we modified HSPs expression to investigate whether HSPs had some effect on ATO induced glioma cell death. Methods: Trypan bule exclusion assay, mitochondrial membrane potential (MMP) Assay, and SubG1 detection were used to evaluate cell viability and western-blot was employed to detect HSPs and some apoptosis markers expression induced by ATO. Heat pre-treatment, HSPs inhibitor, or Heat Shock factor-1 (HSF1) knockdown by SiRNA was employed to modify HSPs levels. Results: It was showed that KNK437 (HSPs inhibitor) or HSF1 knockdown significantly enhanced cell death, MMP disruption, JNK phosphorylation and caspase-3 cleavage induced by ATO, which was accompanied by abrogation of HSPs induction, while heat pre-treatment with clear HSPs induction had strong protection on the effects mentioned above. Conclusion: Those data suggested that HSPs play protective roles on ATO induced cell death in glioma. Inhibition of HSPs may have a synergistic effect with ATO on glioma treatment. RÉSUMÉ: La suppression de la réponse HSP augmente la mort cellulaire induite par As203 dans les lignées cellulaires de gliomes. Objectifs :Nous avons rapporté antérieurement que le trioxyde d'arsenic (TOA) peut inhiber la croissance de gliomes tant in vitro qu'in vivo. Cependant, l'utilisation du TOA seul pour le traitement de tumeurs solides s'avérait parfois inefficace, ce qui pourrait être dû aux voies protectrices telles la réponse aux protéines de choc thermique (HSP) induite par le TOA. Dans cette étude, nous avons modifié l'expression des HSP pour déterminer si les HSP avaient un effet sur la mort de cellules de gliomes induite par le TOA. Méthodes : Le test d'exclusion au bleu trypan, le test de potentiel membranaire mitochondrial (PMM) et la détection de cellules en phase Sub-G1 ont été utilisés pour évaluer la viabilité cellulaire, et le buvardage de western pour détecter les HSP et l'expression de certains marqueurs de l'apoptose induits par le TOA. No...

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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

Cited by 17 publications

References 24 publications

Biological Responses to Arsenic Compounds

Biological Responses to Arsenic Compounds

Down-regulation of heat shock protein 70 improves arsenic trioxide and 17-DMAG effects on constitutive signal transducer and activator of transcription 3 activity

Abrogating HSP Response Augments Cell Death Induced by As2O3 in Glioma Cell Lines

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