Therapeutic Approaches for Targeting Hypoxia- Inducible Factor in Multiple Myeloma

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

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Novel therapeutic approaches for multiple myeloma

Immunological Reviews ◽

10.1034/j.1600-065x.2003.00053.x ◽

2003 ◽

Vol 194 (1) ◽

pp. 164-176 ◽

Cited By ~ 59

Author(s):

Teru Hideshima ◽

Paul Richardson ◽

Kenneth C. Anderson

Keyword(s):

Multiple Myeloma ◽

Therapeutic Approaches ◽

Novel Therapeutic

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Rosiglitazone suppresses angiogenesis in multiple myeloma via downregulation of hypoxia-inducible factor-1α and insulin-like growth factor-1 mRNA expression

Molecular Medicine Reports ◽

10.3892/mmr.2014.2407 ◽

2014 ◽

Vol 10 (4) ◽

pp. 2137-2143 ◽

Cited By ~ 6

Author(s):

MINGZHONG RUI ◽

ZHANPING HUANG ◽

YING LIU ◽

ZIYAN WANG ◽

RUI LIU ◽

...

Keyword(s):

Multiple Myeloma ◽

Growth Factor ◽

Mrna Expression ◽

Hypoxia Inducible Factor ◽

Insulin Like Growth Factor ◽

Hypoxia Inducible Factor 1Α

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Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells

Haematologica ◽

10.3324/haematol.2009.015628 ◽

2009 ◽

Vol 95 (5) ◽

pp. 776-784 ◽

Cited By ~ 54

Author(s):

S. K. Martin ◽

P. Diamond ◽

S. A. Williams ◽

L. B. To ◽

D. J. Peet ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Hypoxia Inducible Factor ◽

Cxcl12 Expression

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Clinical Staging and New Therapeutic Approaches in Multiple Myeloma

Lymphoid Neoplasias II - Recent Results in Cancer Research ◽

10.1007/978-3-642-81249-1_3 ◽

1978 ◽

pp. 12-20 ◽

Cited By ~ 6

Author(s):

S. E. Salmon ◽

B. G. M. Durie

Keyword(s):

Multiple Myeloma ◽

Clinical Staging ◽

Therapeutic Approaches ◽

New Therapeutic Approaches

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Pros and cons of frontline autologous transplant in multiple myeloma: the debate over timing

Blood ◽

10.1182/blood-2018-08-825349 ◽

2019 ◽

Vol 133 (7) ◽

pp. 652-659 ◽

Cited By ~ 11

Author(s):

Shaji K. Kumar ◽

Francis K. Buadi ◽

S. Vincent Rajkumar

Keyword(s):

Multiple Myeloma ◽

The United States ◽

Initial Therapy ◽

Treatment Modalities ◽

Therapeutic Approaches ◽

Geographical Variations ◽

Maximum Benefit ◽

Recent Phase ◽

Pros And Cons ◽

First Relapse

Abstract The treatment landscape for multiple myeloma has dramatically changed over the past decade with the introduction of several new classes of drugs, which are very effective at controlling the disease for prolonged periods of time, especially when used in multidrug combinations. Prior to the advent of these new agents, peripheral blood autologous stem cell transplantation (ASCT) was the mainstay of therapy for patients who were eligible to undergo the procedure, with deep and durable responses in the majority of patients. Despite the introduction of more effective therapies, ASCT continues to play an important role in overall management of younger patients, where it has been integrated with the other therapeutic approaches to provide maximum benefit. Recent phase 3 trials have once again confirmed the survival benefit associated with ASCT in myeloma. Retrospective studies have also demonstrated the feasibility of using ASCT at the time of first relapse rather than as a component of the initial treatment. Significant geographical variations exist in the use of ASCT, especially between the United States and Europe in terms of its use as part of upfront therapy. Much of these differences are driven by the availability of drugs and drug combinations for initial therapy of myeloma as well as maintenance approaches post-ASCT. It is amply clear from these trials that ASCT will continue to play an important role in management of myeloma and is likely to be used as a platform for enhancing the efficacy of other treatment modalities that are currently in development.

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Different Adaptive Responses to Hypoxia in Normal and Multiple Myeloma Endothelial Cells

Cellular Physiology and Biochemistry ◽

10.1159/000488423 ◽

2018 ◽

Vol 46 (1) ◽

pp. 203-212 ◽

Cited By ~ 13

Author(s):

Irene Filippi ◽

Ilaria Saltarella ◽

Carlo Aldinucci ◽

Fabio Carraro ◽

Roberto Ria ◽

...

Keyword(s):

Multiple Myeloma ◽

Endothelial Cells ◽

Cell Survival ◽

Glucose Transporter ◽

Umbilical Vein ◽

Hypoxia Inducible Factor ◽

Monocarboxylate Transporter ◽

Hypoxic Exposure ◽

Adaptive Responses ◽

Pathological Conditions

Background/Aims: Hypoxia is a powerful stimulator of angiogenesis under physiological as well as pathological conditions. Normal endothelial cells (EC), such as human umbilical vein EC (HUVEC), are relatively affected by hypoxic insult in terms of cell survival. In contrast, EC from tumors are particularly resistant to hypoxia-induced cell death. Previous reports have shown that EC in bone marrow from multiple myeloma (MM) patients had a hypoxic phenotype, even under normoxic conditions. The aim of this study was to evaluate whether HUVEC and MMEC adapt differently to hypoxia. Methods: Cell proliferation was assessed by the CyQUANT assay. Cdc25A, p21, Bax, Bcl-xl, BNIP3, glucose transporter (GLUT)-1, monocarboxylate transporter (MCT)-4 and carbonic anhydrase (CA)IX mRNA expression was determined by qRT-PCR. HIF-1α, BNIP3, Beclin-1, LC3B, livin, Bax, Bcl-xl, p21, p62 and β-actin protein expression was analyzed by western blot. Apoptosis was determined by TUNEL assay. Silencing of BNIP3 was achieved by stealth RNA system technology. Results: While HUVEC survival was reduced after prolonged hypoxic exposure, MMEC were completely unaffected. This difference was also significant in terms of livin, cdc25A and p21 expression. Hypoxia induced apoptosis and inhibited autophagy in HUVEC, but not in MMEC, where hypoxic treatment resulted in a more sustained adaptive response. In fact, MMEC showed a more significant increase in the expression of genes regulated transcriptionally by hypoxia-inducible factor (HIF)-1α. Interestingly, they showed higher expression of BNIP3 than did HUVEC, indicating a more pronounced autophagic (and pro-survival) phenotype. The potential role of BNIP3 in EC survival was confirmed by BNIP3 siRNA experiments in HUVEC, where BNIP3 inhibition resulted in reduced cell survival and increased apoptosis. Conclusion: These findings provide further information on how hypoxia may affect EC survival and could be important for a better understanding of EC physiology under normal and pathological conditions, such as in multiple myeloma.

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