ATP Analog Enhances the Actions of a Heat Shock Protein 90 Inhibitor in Multiple Myeloma Cells

Cervantes-Gomez, Fabiola; Nimmanapalli, Ramadevi; Gandhi, Varsha

doi:10.1124/jpet.111.184903

Cited by 6 publications

(5 citation statements)

References 38 publications

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“…In the present study, we demonstrated that the RNA and protein levels of HSPs expressed on most of the primary myeloma cells were dramatically higher than that expressed on normal cells, in line with other results (Duus et al , ; Cervantes‐Gomez et al , ). Of the large number of HSP previously studied, RNA and protein over‐expression of HSPs had been repeatedly found in all of the MM cell lines used in our investigations, such as U266, RPMI 8226, ARH‐77, LP‐1and the primary myeloma cells from all MM patient's samples (Duus et al , ; Cervantes‐Gomez et al , ), strongly suggesting that HSPs were myeloma TAA. Hence, it was possible to use HSPs as a selective target in myeloma cells.…”

Section: Discussionsupporting

confidence: 93%

“…Furthermore, HSPs are abundantly and preferentially expressed in MM cells and are two‐ to 10‐fold higher than their normal counterparts (Chauhan et al , , ; De Vos et al , ). Of the large number of HSPs previously studied, over‐expression of HSP RNA and HSPs proteins has been repeatedly found in MM cell lines such as U266, RPMI 8226, ARH‐77, LP‐1and the primary neoplastic plasma cells from all MM patient samples (Duus et al , ; Cervantes‐Gomez et al , ). Studies observed that HSPs in an activated, high‐affinity conformation, as contained in tumour cells, were obviously different from that latent, uncomplexed state in normal cells (Kamal et al , ) and allowed a selective targeting of the molecules in cancer cells.…”

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confidence: 99%

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Human heat shock protein-specific cytotoxic T lymphocytes display potent antitumour immunity in multiple myeloma

Qian

Zhang

et al. 2014

Br J Haematol

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Tumour cell–derived heat shock proteins (HSPs) are used as vaccines for immunotherapy of cancer patients. However, it is proposed that the peptide chaperoned on HSPs, not HSPs themselves, elicited a potent immune response. Given that HSPs are highly expressed by most myeloma cells and vital to myeloma cell survival, we reasoned that HSPs themselves might be an ideal myeloma antigen. In the present study, we explored the feasibility of targeting HSPs themselves for treating multiple myeloma. We identified and chose HLA-A*0201-binding peptides from human HSPB1 (HSP27) and HSP90AA1 (HSP90), and confirmed their immunogenicity in HLA-A*0201 transgenic mice. Dendritic cells pulsed with HSPB1 and HSP90AA1 peptides were used to stimulate peripheral blood mononuclear cells from healthy volunteers and myeloma patients to generate HSP peptide-specific cytotoxic T lymphocytes (CTLs). HSP peptide-specific CTLs efficiently lysed HLA-A*0201+ myeloma cells (established cell lines and primary plasma cells) but not HLA-A*0201− myeloma cells in vitro, indicating that myeloma cells naturally express HSP peptides in the context of major histocompatibility complex class I molecules. More importantly, HSP peptide-specific CTLs effectively reduced tumour burden in the xenograft mouse model of myeloma. Our study clearly demonstrated that HSPs might be novel tumour antigens for immunotherapy of myeloma.

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Section: Discussionsupporting

confidence: 93%

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confidence: 99%

Human heat shock protein-specific cytotoxic T lymphocytes display potent antitumour immunity in multiple myeloma

Qian

Zhang

et al. 2014

Br J Haematol

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“…As illustrated in Figure 1A , the sensitive MM.1S and JeKo cell lines exhibit LC 50 concentrations of less than 3 µM whereas cell death in the resistant cell lines U266 and Granta 519 does not reach 50% with concentrations of 8-NH 2 -Ado ranging up to 10 µM. Importantly, these four cell lines also display differential sensitivity to 8-Cl-Ado [4] , [19] , indicating that intrinsic resistance mechanisms to common activities of both analogues are at play only in the U266 and Granta 519 cell lines. RNA isolated from each of the four cell lines was labeled and hybridized to Illumina Human-HT12 BeadChip microarrays.…”

Section: Resultsmentioning

confidence: 98%

Integrative Gene Expression Profiling Reveals G6PD-Mediated Resistance to RNA-Directed Nucleoside Analogues in B-Cell Neoplasms

et al. 2012

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The nucleoside analogues 8-amino-adenosine and 8-chloro-adenosine have been investigated in the context of B-lineage lymphoid malignancies by our laboratories due to the selective cytotoxicity they exhibit toward multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL) cell lines and primary cells. Encouraging pharmacokinetic and pharmacodynamic properties of 8-chloro-adenosine being documented in an ongoing Phase I trial in CLL provide additional impetus for the study of these promising drugs. In order to foster a deeper understanding of the commonalities between their mechanisms of action and gain insight into specific patient cohorts positioned to achieve maximal benefit from treatment, we devised a novel two-tiered chemoinformatic screen to identify molecular determinants of responsiveness to these compounds. This screen entailed: 1) the elucidation of gene expression patterns highly associated with the anti-tumor activity of 8-chloro-adenosine in the NCI-60 cell line panel, 2) characterization of altered transcript abundances between paired MM and MCL cell lines exhibiting differential susceptibility to 8-amino-adenosine, and 3) integration of the resulting datasets. This approach generated a signature of seven unique genes including G6PD which encodes the rate-determining enzyme of the pentose phosphate pathway (PPP), glucose-6-phosphate dehydrogenase. Bioinformatic analysis of primary cell gene expression data demonstrated that G6PD is frequently overexpressed in MM and CLL, highlighting the potential clinical implications of this finding. Utilizing the paired sensitive and resistant MM and MCL cell lines as a model system, we go on to demonstrate through loss-of-function and gain-of-function studies that elevated G6PD expression is necessary to maintain resistance to 8-amino- and 8-chloro-adenosine but insufficient to induce de novo resistance in sensitive cells. Taken together, these results indicate that G6PD activity antagonizes the cytotoxicity of 8-substituted adenosine analogues and suggests that administration of these agents to patients with B-cell malignancies exhibiting normal levels of G6PD expression may be particularly efficacious.

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“…A 2A adenosine and β-2 adrenergic receptors have synergistic anti-proliferative activity in multiple myeloma models [338]. Heat shock protein 90 (HSP90) is over-expressed in multiple myeloma and 8-chloro-adenosine is currently in clinical trials as an enhancer of inhibition HSP90 to treat multiple myeloma [339].…”

Section: Myelomamentioning

confidence: 99%

Purinergic signalling and cancer

Burnstock

Virgilio

2013

Purinergic Signalling

269

265

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Receptors for extracellular nucleotides are widely expressed by mammalian cells. They mediate a large array of responses ranging from growth stimulation to apoptosis, from chemotaxis to cell differentiation and from nociception to cytokine release, as well as neurotransmission. Pharma industry is involved in the development and clinical testing of drugs selectively targeting the different P1 nucleoside and P2 nucleotide receptor subtypes. As described in detail in the present review, P2 receptors are expressed by all tumours, in some cases to a very high level. Activation or inhibition of selected P2 receptor subtypes brings about cancer cell death or growth inhibition. The field has been largely neglected by current research in oncology, yet the evidence presented in this review, most of which is based on in vitro studies, although with a limited amount from in vivo experiments and human studies, warrants further efforts to explore the therapeutic potential of purinoceptor targeting in cancer.

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ATP Analog Enhances the Actions of a Heat Shock Protein 90 Inhibitor in Multiple Myeloma Cells

Cited by 6 publications

References 38 publications

Human heat shock protein-specific cytotoxic T lymphocytes display potent antitumour immunity in multiple myeloma

Human heat shock protein-specific cytotoxic T lymphocytes display potent antitumour immunity in multiple myeloma

Integrative Gene Expression Profiling Reveals G6PD-Mediated Resistance to RNA-Directed Nucleoside Analogues in B-Cell Neoplasms

Purinergic signalling and cancer

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