The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance

Meinel, Felix G.; Mandl-Weber, Sonja; Baumann, Philipp; Leban, Johann; Schmidmaier, Ralf

doi:10.1158/1535-7163.mct-09-0645

Cited by 17 publications

(8 citation statements)

References 44 publications

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“…In addition, perifosine, an Akt inhibitor, enhances the cytotoxicity of dexamethasone, melphalan, or doxorubicin in MM cell lines [38]. Alkylating agent-induced NF-κB activation is associated with chemoresistance, and suppression of NF-κB reverses the sensitivity to alkylating agents [39,40]. Together, our previous study and this one show that, in melphalan-resistant cells, phosphorylation of c-Src induces ERK1/2, Akt, and NF-κB activation, and inhibition of c-Src by dasatinib resensitizes the cells to melphalan [31].…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Thus, the repression of p21 WAF1/CIP1 by RSK2 may contribute to both cytotoxicity and inhibition of cell proliferation as a result of cyclin destabilization. MCL1 is a member of the antiapoptotic BCL2 family of proteins and, as the downstream effector molecule of various signal pathways such as IL-6 or nuclear factor kappa-B, promotes cell survival and drug resistance in multiple myeloma (38,39). MCL1 repression caused by RSK2 inhibition may thus be involved in apoptosis induction and may also be beneficial for overcoming drug resistance and for preventing disease progression.…”

Section: Inhibition Of Rsk2mentioning

confidence: 99%

RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma

Shimura

Kuroda

et al. 2012

Molecular Cancer Therapeutics

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Multiple myeloma is an entity of cytogenetically and genetically heterogenous plasma cell neoplasms. Despite recent improvement in the treatment outcome of multiple myeloma by novel molecular-targeted chemotherapeutics, multiple myeloma remains incurable. The identification of a therapeutic target molecule in which various signaling for cell-survival converge is a core component for the development of new therapeutic strategies against multiple myeloma. RSK2 is an essential mediator of the ERK1/2 signaling pathway for cell survival and proliferation. In this study, we discovered that RSK2 Ser227 , which is located at the N-terminal kinase domain and is one site responsible for substrate phosphorylation, is activated through phosphorylation regardless of the type of cytogenetic abnormalities or upstream molecular signaling in all 12 multiple myeloma-derived cell lines examined and 6 of 9 patient-derived CD138-positive primary myeloma cells. The chemical inhibition of RSK2Ser227 by BI-D1870 or gene knockdown of RSK2 inhibits myeloma cell proliferation through apoptosis induction, and this anti-myeloma effect was accompanied by downregulation of c-MYC, cyclin D, p21 WAF1/CIP1 , and MCL1. RSK2 Ser227 inhibition resulting from BI-D1870 treatment restored lenalidomide-induced direct cytotoxicity of myeloma cells from interleukin-6-mediated cell protection, showed no cross-resistance to bortezomib, and exerted additive/synergistic antiproliferative effects in conjunction with the mTOR, histone deacetylase, and BH3-mimicking BCL2/BCLX L inhibitors. These results suggest that RSK2 Ser227 is a potential therapeutic target not only for newly diagnosed but also for patients with later phase multiple myeloma who are resistant or refractory to currently available anti-myeloma therapies.

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“…MM is also associated with osteoclast activation and osteoblast suppression that can lead to lytic bone lesions, as well as the damage of end-organs, could induce anemia, immunodeficiency and renal dysfunction [3]. Although the existing therapies such as bortezomib, thalidomide and lenalidomide can enhance remission rates and prolong survival of MM patients, MM is still regarded as incurable due to the common development of drug resistance and therapeutic complications associated with the disease [4]. Therefore, it is necessary to establish novel effective therapies to treat MM.…”

Section: Introductionmentioning

confidence: 99%

Pterostilbene Inhibits Human Multiple Myeloma Cells via ERK1/2 and JNK Pathway In Vitro and In Vivo

Xie

et al. 2016

IJMS

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Multiple myeloma (MM) is the second most common malignancy in the hematologic system, which is characterized by accumulation of plasma cells in bone marrow. Pterostilbene (PTE) is a natural dimethylated analog of resveratrol, which has anti-oxidant, anti-inflammatory and anti-tumor properties. In the present study, we examined the anti-tumor effect of PTE on MM cell lines both in vitro and in vivo using the cell counting kit (CCK)-8, apoptosis assays, cell cycle analysis, reactive oxygen species (ROS) generation, JC-1 mitochondrial membrane potential assay, Western blotting and tumor xenograft models. The results demonstrated that PTE induces apoptosis in the H929 cell line and causes cell cycle arrest at G0/G1 phase by enhancing ROS generation and reducing mitochondrial membrane potential. The anti-tumor effect of PTE may be caused by the activation of the extracellular regulated protein kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK) signaling pathways. Additionally, mice treated with PTE by intraperitoneal injection demonstrated reduced tumor volume. Taken together, the results of this study indicate that the anti-tumor effect of PTE on MM cells may provide a new therapeutic option for MM patients.

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The Novel, Proteasome-Independent NF-κB Inhibitor V1810 Induces Apoptosis and Cell Cycle Arrest in Multiple Myeloma and Overcomes NF-κB–Mediated Drug Resistance

Cited by 17 publications

References 44 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

RSK2Ser227 at N-Terminal Kinase Domain Is a Potential Therapeutic Target for Multiple Myeloma

Pterostilbene Inhibits Human Multiple Myeloma Cells via ERK1/2 and JNK Pathway In Vitro and In Vivo

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