Synergistic action of the novel HSP90 inhibitor NVP‐AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma

Kaiser, Martin; Lamottke, Britta; Mieth, Maren; Jensen, Michael Rugaard; Quadt, Cornelia; García‐Echeverría, Carlos; Atadja, Peter; Heider, Ulrike; Metzler, Ivana von; Türkmen, Seval; Sezer, Orhan

doi:10.1111/j.1600-0609.2009.01403.x

Cited by 40 publications

(37 citation statements)

References 28 publications

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“…In other tumor entities, HSP90 inhibitors enhanced the effect of doxorubicin or 5-FU in vitro (Burkitt et al 2007, Abramson et al 2009, Kaiser et al 2010. For PET, we could demonstrate similar effects.…”

Section: Endocrine-related Cancersupporting

confidence: 62%

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

Mayer

Harjung²,

Breinig³

et al. 2011

Endocrine-Related Cancer

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Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat-shock protein (HSP) 90 was investigated in 120 clinically and pathomorphologically well-characterized PET from 84 patients using immunohistochemistry. In addition, in 19 snap-frozen PET and in three healthy pancreatic tissues, we performed immunoblot analyses, and in 15 snap-frozen PET and in three healthy pancreatic tissues, we investigated the expression of HSP90 isoforms by means of semiquantitative RT-PCR. Functional tests were conducted using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line b-TC-3. HSP90 was expressed in 95% of the PET patients. The transcript levels of the HSP90 isoforms HSP90a, HSP90b, glucose-related protein 94, and TNF receptor-associated protein 1 were significantly increased in PET compared with non-neoplastic pancreatic tissues. The treatment of the cell lines BON and b-TC-3 with the HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin resulted in significant, dose-dependent reduction of cell viability, cell cycle arrest, and increased apoptosis. Furthermore, HSP90 inhibition induced the degradation and inactivation of several oncogenetic HSP90 client proteins in a time-and dose-dependent manner. HSP90 inhibitors increased the therapeutic effects of doxorubicin and 5-fluorucacil in BON and b-TC-3 cells. HSP90 is expressed in the vast majority of PET and its inhibition reveals significant treatment effects in vitro. Thus, HSP90 qualifies as a promising new target.

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Section: Endocrine-related Cancersupporting

confidence: 62%

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

Mayer

Harjung²,

Breinig³

et al. 2011

Endocrine-Related Cancer

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“…96 Similarly, the orally available NVP-BEP800 was able to induce apoptosis in myeloma cell lines and primary patient samples with pronounced inhibition of the STAT3, ERK and Akt pathways. Weak synergy was demonstrated with melphalan whereas combinations with bortezomib, doxorubicin or SAHA were weakly antagonistic.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 98%

“…95 It also demonstrated synergy with histone deacetylase inhibitors, melphalan and doxorubicin in primary patient samples refractory to conventional therapies. 96 Similarly, the orally available NVP-BEP800 was able to induce apoptosis in myeloma cell lines and primary patient samples with pronounced inhibition of the STAT3, ERK and Akt pathways. Weak synergy was demonstrated with melphalan whereas combinations with bortezomib, doxorubicin or SAHA were weakly antagonistic.…”

Section: Heat-shock Chaperone Inhibitorsmentioning

confidence: 98%

DangER: protein ovERload. Targeting protein degradation to treat myeloma

Aronson¹,

Davies²

2012

Haematologica

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Myeloma is a malignancy of the antibody-producing plasma cells and, as such, these cells synthesize large quantities of unfolded or misfolded immunoglobulin. The build-up of excess protein triggers a number of downstream signal transduction cascades, including endoplasmic reticulum stress and autophagy. As a result, myeloma cells are uniquely reliant on these and other protein handling pathways for their survival. Strategies aimed at targeting this vulnerability have proved successful with the proteasome inhibitor, bortezomib, already licensed for clinical use. In addition to the proteasome, various other points within the protein handling pathways are also the subject of drug discovery projects, with some already progressing into clinical trials. These include compounds directed against heat shock proteins, the unfolded protein response and pathways both upstream and downstream of the proteasome.More recently, the role of autophagy has been recognized in myeloma. In this review, we discuss the various pathways used by myeloma cells for survival, with particular emphasis on the emerging role and conundrum of autophagy, as well as highlighting pre-clinical research on novel inhibitors targeting protein handling pathways.Key words: autophagy, proteasome, ER stress, heat-shock chaperones, unfolded protein response.Citation: Aronson LI and Davies FE. DangER: protein ovERload. Targeting protein degradation to treat myeloma. Haematologica 2012;97(8):1119-1130. doi:10.3324/haematol.2012 This is an open-access paper. ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nbeen extensively reviewed and so will not be covered further here. 7,8 We aim to provide an overview of the protein handling and stress response pathways. We highlight the potential points in these pathways that can be targeted therapeutically, and review the supporting pre-clinical data. Protein handling pathwaysUnder normal conditions, the synthesis, folding and degradation of cellular proteins are balanced processes. In myeloma cells, however, the protein folding capacity of the endoplasmic reticulum (ER) is overloaded by large quantities of immunoglobulin and cells must adapt to this continual stress. 9 A close relationship with common signaling nodes therefore exists between the ubiquitin proteasome pathway, cellular stress pathways such as the unfolded protein response (UPR), heat shock response and autophagy. Ubiquitin proteasome pathwayThe main cellular pathway for the removal and destruction of proteins is the ubiquitin proteasome pathway. This involves the sequential enzymatic transfer of ubiquitin monomers onto an elongating polyubiquitin chain bound at the lysine 11 or lysine 48 residues of target proteins. 10 In the first step of this cascade, an E1 activating enzyme, typically ubiquitin activating enzyme (UAE, also known as UBA1), binds ubiquitin. A second ubiquitin monomer binds to a different site on the E1 enzyme and the first ubiquitin is transferred to an E2 ubiquitin-conjugating enzyme. The final step involves the transfer of ubiq...

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“…Moreover, NVP-AUY922 in combination with histone deacetylase inhibitors SAHA, NVP-LBH589, melphalan or doxorubicin resulted in synergistic inhibition of viability, with strong synergy (combination index <0.3) in the case of melphalan. Importantly, resistance of the RPMI-8226 cell line and relative resistance of some primary myeloma cells against NVP-AUY922 could be overcome by combination treatment (120). in this manner, the p38 MAPK inhibitor BiRB 796, inhibited protein expression and phosphorylation of Hsp27 induced by Hsp90 inhibitor 17-AAG and enhanced its cytotoxicity (121).…”

Section: Combination Of Hsp90 Inhibitor With Second Therapymentioning

confidence: 99%

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

Solárová¹,

Mojžiš²,

Solár³

2014

Int J Oncol

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Abstract. Hsp90 is a molecular chaperone that maintains the structural and functional integrity of various client proteins involved in signaling and many other functions of cancer cells. The natural inhibitors, ansamycins influence the Hsp90 chaperone function by preventing its binding to client proteins and resulting in their proteasomal degradation. Nand C-terminal inhibitors of Hsp90 and their analogues are widely tested as potential anticancer agents in vitro, in vivo as well as in clinical trials. It seems that Hsp90 competitive inhibitors target different tumor types at nanomolar concentrations and might have therapeutic benefit. On the contrary, some Hsp90 inhibitors increased toxicity and resistance of cancer cells induced by heat shock response, and through the interaction of survival signals, that occured as side effects of treatments, could be very effectively limited via combination of therapies. The aim of our review was to collect the data from experimental and clinical trials where Hsp90 inhibitor was combined with other therapies in order to prevent resistance as well as to potentiate the cytotoxic and/or antiproliferative effects.

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Synergistic action of the novel HSP90 inhibitor NVP‐AUY922 with histone deacetylase inhibitors, melphalan, or doxorubicin in multiple myeloma

Cited by 40 publications

References 28 publications

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

DangER: protein ovERload. Targeting protein degradation to treat myeloma

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

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