The anti-tumoral effect of lenalidomide is increased in vivo by hypoxia-inducible factor (HIF)-1  inhibition in myeloma cells

Storti, Paola; Toscani, Denise; Airoldi, Irma; Marchica, Valentina; Maïga, Sophie; Bolzoni, Marina; Fiorini, Elena; Campanini, Nicoletta; Martella, Eugenia; Mancini, Cristina; Guasco, Daniela; Ferri, Valentina; Donofrío, Gaetano; Aversa, Franco; Amiot, Martine; Giuliani, Nicola

doi:10.3324/haematol.2015.133736

Cited by 13 publications

(11 citation statements)

References 15 publications

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“…In addition, hypoxia conditions enhanced tumor initiation and induced resistance to bortezomib and carfilzomib in MM cells [53,54]. It was also reported that downregulation of HIF-1α expression enhanced sensitivity to bortezomib and lenelidomide [55,56]. Furthermore, we found that our established melphalan-resistant MM cells showed decreased sensitivity to bortezomib (data not shown).…”

Section: Discussionsupporting

confidence: 54%

Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB

Tsubaki

Takeda

Tomonari

et al. 2019

Laboratory Investigation

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Multiple myeloma (MM) commonly displays multidrug resistance and is associated with poor prognosis. Therefore, it is important to identify the mechanisms by which MM cells develop multidrug resistance. Our previous study showed that multidrug resistance is correlated with overexpression of multidrug resistance protein 1 (MDR1) and Survivin, and downregulation of Bim expression in melphalan-resistant RPMI8226/L-PAM cells; however, the underlying mechanism of multidrug resistance remains unclear. In the present study, we investigated the mechanism of multidrug resistance in melphalan-resistant cells. We found that RPMI8226/L-PAM and ARH-77/L-PAM cells showed increased phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK1/2) and Akt, and nuclear localization of nuclear factor κB (NF-κB). The combination of ERK1/2, Akt, and NF-κB inhibitors with melphalan reversed melphalan resistance via suppression of Survivin expression and enhanced Bim expression in melphalan-resistant cells. In addition, RPMI8226/L-PAM and ARH-77/L-PAM cells overexpressed hypoxia-inducible factor 1α (HIF-1α) via activation of ERK1/2, Akt, and NF-κB. Moreover, suppression of HIF-1α by echinomycin or HIF-1α siRNA resensitized RPMI8226/L-PAM cells to melphalan through downregulation of Survivin expression and upregulation of Bim expression. These results indicate that enhanced Survivin expression and decreased Bim expression by HIF-1α via activation of ERK1/2, Akt, and NF-κB play a critical role in melphalan resistance. Our findings suggest that HIF-1α, ERK1/2, Akt, and NF-κB inhibitors are potentially useful as anti-MDR agents for the treatment of melphalan-resistant MM.

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Section: Discussionsupporting

confidence: 54%

Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB

Tsubaki

Takeda

Tomonari

et al. 2019

Laboratory Investigation

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“…Therefore, IMiDs may be effective even in myeloma cells with an immature phenotype and low IRF4 expression under hypoxic conditions. Recently, it was reported that the combined use of lenalidomide and HIF inhibition induced a synergistic effect in a myeloma‐xenografted model 72 . This study suggested that treatment with IMiDs alone may have incomplete efficacy against myeloma cells that express high levels of HIF.…”

Section: Impact Of Hypoxia On Treatment Resistancementioning

confidence: 91%

“…Recently, it was reported that the combined use of lenalidomide and HIF inhibition induced a synergistic effect in a myeloma‐xenografted model. 72 This study suggested that treatment with IMiDs alone may have incomplete efficacy against myeloma cells that express high levels of HIF. Therefore, future studies must involve a detailed examination to determine the relationship between cereblon modulators and HIFs.…”

Section: Impact Of Hypoxia On Treatment Resistancementioning

confidence: 94%

Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma

Ikeda

Tagawa

2021

Cancer Science

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“…It is impossible to cite all the publications that have used this approach to downregulate galectins in this review; we only mention a few examples. Indeed, RNA interference was often used to confirm basic aspects of tumor biology (which includes intrinsic effects on the transformed cells themselves (88-91, 99-101, 103, 237, [248][249][250][251][252][253][254][255][256][257][258], the modulation of the tumor-associated stroma (80,96,97,201,(259)(260)(261)(262)(263)(264)(265) and, importantly, as a synergic therapy option for cancer (37,42,92,98,101,102,104,(266)(267)(268)(269)(270). Several properties of this gene control strategy deserve to be highlighted compared to the aforementioned galectin inhibitors.…”

Section: Negative Control Of Galectin Gene Expression (Ablation Of Al...mentioning

confidence: 99%

Inhibition of galectins in cancer: Biological challenges for their clinical application

Laderach

Compagno

2023

Front. Immunol.

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Galectins play relevant roles in tumor development, progression and metastasis. Accordingly, galectins are certainly enticing targets for medical intervention in cancer. To date, however, clinical trials based on galectin inhibitors reported inconclusive results. This review summarizes the galectin inhibitors currently being evaluated and discusses some of the biological challenges that need to be addressed to improve these strategies for the benefit of cancer patients.

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The anti-tumoral effect of lenalidomide is increased in vivo by hypoxia-inducible factor (HIF)-1 inhibition in myeloma cells

Cited by 13 publications

References 15 publications

Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB

Overexpression of HIF-1α contributes to melphalan resistance in multiple myeloma cells by activation of ERK1/2, Akt, and NF-κB

Impact of hypoxia on the pathogenesis and therapy resistance in multiple myeloma

Inhibition of galectins in cancer: Biological challenges for their clinical application

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