Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma

Yang, Wen-Chi; Lin, Sheng-Fung

doi:10.1155/2015/341430

Cited by 56 publications

(52 citation statements)

References 233 publications

(223 reference statements)

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“…We considered that this differential susceptibility to HVJ-E might result from different expression of genes targeted by HVJ-E, which determine cell fate. Previous studies demonstrated that aberrant c-Myc expression is associated with myeloma cell survival and proliferation [2, 5]. Therefore, we focused on the regulation of c-Myc expression in HVJ-E-treated MM cells.…”

Section: Resultsmentioning

confidence: 99%

“…However, one major limitation of the existing drugs is the eventual emergence of drug resistance for nearly all patients, regardless of the treatment regimen or the initial response to treatment [3]. It is well known that bone marrow microenvironment changes, such as cell adhesion and cytokine-related induction of the JAK/STAT and PI3K/AKT pathways, are responsible for resistance to conventional and novel therapies [4, 5]. Because MM is characterized by a high level of genomic instability and complex cytogenetic aberrations [6, 7], many of these alterations, which include chromosomal translocation, methylation, gene mutation, and microRNA (miRNA) abnormalities, can contribute to drug resistance [3, 8, 9].…”

Section: Introductionmentioning

confidence: 99%

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Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene

et al. 2016

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Because the emergence of drug resistance is a major limitation of current treatments for multiple myeloma (MM), it is necessary to continuously develop novel anticancer strategies. Here, using an inactivated Sendai virus (Hemagglutinating Virus of Japan; HVJ) envelope (HVJ-E), we discovered that increase of cytoplasmic Ca2+ by virus-cell fusion significantly induced apoptosis against human MM cells but not peripheral blood mononuclear cells from healthy donors. Interaction of F protein of HVJ-E with MM cells increased intracellular Ca2+ level of MMs by the induction of Ca2+ efflux from endoplasmic reticulum but not influx from extracellular region. The elevation of the Ca2+ cytoplasmic level induced SMAD1/5/8 phosphorylation and translocation into the nucleus, and SMAD1/5/8 and SMAD4 complex suppressed c-Myc transcription. Meanwhile, HVJ-E decreases S62 phosphorylation of c-Myc and promotes c-Myc protein degradation. Thus, HVJ-E-induced cell death of MM resulted from suppression of c-Myc by both destabilization of c-Myc protein and downregulation of c-Myc transcription. This study indicates that HVJ-E will be a promising tool for MM therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene

et al. 2016

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“…On the other hand, the development of drug-resistance in some hematological tumors, for example in CML (An et al, 2010), and the lack of effective treatments in other ones (Martelli et al, 2012; Yang and Lin, 2015; Zinzani et al, 2015), addressed researchers to the study of new molecular targets and innovative therapeutic agents.…”

Section: Introdutionmentioning

confidence: 99%

A Pyrazolo[3,4-d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies

et al. 2016

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Molecular targeted therapies are based upon drugs acting on tumors by interfering with specific targets involved in growth and spread of cancer. Many targeted therapies were approved by Food and Drug Administration as standard treatment, others were introduced into preclinical or clinical studies on hematological malignancies (HMs). The development of drug-resistance in some HMs and the lack of effective treatments in other ones emphasized the need for searching new molecular targets and therapeutic agents. The aim of this study was to evaluate the effects of 4c pyrazolo[3,4-d]pyrimidine compound, a Src inhibitor, on lymphoid and myeloid neoplasms. Here, we demonstrated its ability to reduce cell viability, induce apoptosis and cell cycle arrest in lymphoid cell lines such as Jurkat, SKMM1, Derl-2/7, and myeloid cell lines, such as Jurl-MK1. Moreover, we reported a high expression of a Src kinase, Fyn, in these cell lines compared to healthy subjects. This study was a starting point to investigate 4c pyrazolo[3,4-d]pyrimidine compound as a drug for HMs and Src kinases as its potential molecular targets.

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“…In the pathogenesis of numerous malignancies the roles of NF‐κB pathway have been documented in many cases . The activity of this cascade in tumour cells leads to the generation of many factors . Inhibitor of nuclear factor kappa‐B kinase (IKKb) is a key molecule in the NF‐κB pathway and regulates pro‐inflammatory activity of this pathway through phosphorylation and proteasomal degradation of the NF‐κB inhibitor (I‐κB) .…”

Section: Introductionmentioning

confidence: 99%

Bone marrow ‐ mesenchymal stem cells impact on the U937 cells in the presence of staphylococcal enterotoxin B (SEB)

Ejtehadifar

Halabian

Ghazavi

et al. 2018

Clin Exp Pharma Physio

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The growing resistance against conventional chemotherapy in acute myeloid leukemia (AML) is a noticeable clinical concern. Therefore, many researchers are looking for novel substances to overcome drug resistance in cancer. Staphylococcal enterotoxin B (SEB) is a superantigen (SAg) and a promising compound which has lethal effects on malignant cells. In this unprecedented study, SEB was used against U937 cells in a co-culture system in the presence of human bone marrow-mesenchymal stem cells (hBM-MSCs). The effects of hBM-MSCs on the proliferation and survival of U937 cell line with SEB was assessed using MTT assay and AnnexinV/PI flowcytometry, respectively. Moreover, the expression of IL-6, IL-10, TGF-β, and inhibitor of nuclear factor kappa-B kinase (IKKb) was evaluated by real-time PCR technique. The same experiments were also carried out using hBM-MSCs-conditioned medium (hBM-MSCs-CM). The results showed that SEB reduced the proliferation and survival of U937 cell line, but hBM-MSCs or hBM-MSCs-CM suppressed the effects of SEB. Furthermore, real-timePCR demonstrated that SEB could decrease the expression of IL-6, IL-10, and TGF-β in hBM-MSCs (P < .05), while the production of IKKb was increased in comparison with the control group. These findings help us to have a broader understanding ofthe usage of SEB in the treatment of haematological malignancies, especially if it is targeted against hBM-MSCs to disrupt their supportive effects on malignant cells.

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Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma

Cited by 56 publications

References 233 publications

Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene

Cytoplasmic calcium increase via fusion with inactivated Sendai virus induces apoptosis in human multiple myeloma cells by downregulation of c-Myc oncogene

A Pyrazolo[3,4-d]pyrimidine Compound Reduces Cell Viability and Induces Apoptosis in Different Hematological Malignancies

Bone marrow ‐ mesenchymal stem cells impact on the U937 cells in the presence of staphylococcal enterotoxin B (SEB)

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