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Hazlehurst, Lori A.; Dalton, William S.

doi:10.1023/a:1013156407224

Cited by 146 publications

(64 citation statements)

References 46 publications

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“…Activation of Wnt/␤-catenin was also responsible for cell adhesion-mediated drug resistance to anthracyclines in neuroblastomas (34), acute myeloid leukemia (35), and myeloma (36). Given this background, and the important role of cell adhesion-mediated drug resistance in the natural history of myeloma (37,38), it is tempting to speculate that Wnt/␤-catenin signaling mediates lenalidomide resistance by impacting on plasma cell adhesive properties. This possibility is supported by the observation that lenalidomide-resistant cells appear to form aggregates to a greater extent than their drug-naive counterparts (data not shown), and we are currently performing further studies to identify the mechanisms behind this morphologic change.…”

Section: Discussionmentioning

confidence: 99%

Evidence of a Role for Activation of Wnt/β-Catenin Signaling in the Resistance of Plasma Cells to Lenalidomide

Bjorklund¹,

Ma²,

Wang³

et al. 2011

Journal of Biological Chemistry

117

110

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Lenalidomide plays an important role in our chemotherapeutic armamentarium against multiple myeloma, in part by exerting direct anti-proliferative and pro-apoptotic effects. Unfortunately, long-term exposure leads to the development of drug resistance through unknown mechanisms, and we therefore sought to identify pathways that could be responsible for this phenotype. Chronic drug exposure produced myeloma cell lines that were tolerant of the direct effects of lenalidomide, with a degree of resistance of up to 2,500-fold. Gene expression profiling and pathway analysis identified dysregulation of the Wnt/␤-catenin pathway as a consistent change across four independent cell isolates, and a pair of primary plasma cell samples. Acute drug treatment also increased ␤-catenin transcription by 3-fold or more, and both acute and chronic exposure resulted in enhanced accumulation of ␤-catenin protein by up to 20-fold or more. This produced Wnt/␤-catenin pathway activation, as judged by increased activity of a lymphoid enhancer factor/T-cell factor promoter reporter, and enhanced accumulation of the downstream targets cyclin D1 and c-Myc. Components of the ␤-catenin destruction complex were also impacted by lenalidomide, which suppressed casein kinase 1␣ expression while augmenting glycogen synthase kinase 3␣/␤ phosphorylation. Stimulation of Wnt/␤-catenin signaling with recombinant Wnt-3a, or by overexpression of ␤-catenin, reduced the anti-proliferative activity of lenalidomide. Conversely, suppression of ␤-catenin with small hairpin RNAs restored plasma cell sensitivity to lenalidomide. Together, these findings support the hypothesis that lenalidomide mediates activation of Wnt/␤-catenin signaling in plasma cells as a mechanism of inducible chemoresistance through effects at the transcriptional and post-translational levels.

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Section: Discussionmentioning

confidence: 99%

Evidence of a Role for Activation of Wnt/β-Catenin Signaling in the Resistance of Plasma Cells to Lenalidomide

Bjorklund¹,

Ma²,

Wang³

et al. 2011

Journal of Biological Chemistry

117

110

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“…Adhesion of myeloma cells to fibronectin through β1 integrins, whose activation is known to influence apoptosis and cell growth, results in CAM-DR. The adhesion leads to a G1 arrest associated with increased p27kip1 expression and inhibition of cyclin A and E kinase activity; disruption of this interaction returns the tumor cells to a drug-sensitive state [62]. Tumor cells also form polarized, three-dimensional structures through interactions with the basement membrane and ligation of β4 integrins, which regulate polarity and NF-κB activation.…”

Section: Mechanisms Of Drug Resistancementioning

confidence: 99%

Nanomedicine therapeutic approaches to overcome cancer drug resistance

Markman

Rekechenetskiy

Holler

et al. 2013

Advanced Drug Delivery Reviews

616

389

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Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a complicated process that involves multiple mechanisms. Here we discuss the major forms of drug resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic profiles can be created making drug selection for personal patient treatment much more intensive and effective. This review aims to demonstrate the advantage of the young medical science field of nanomedicine for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers, carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks promising and opens new horizons for cancer treatment.

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“…An important consequence of these direct adhesive interactions between the BM/ECM and MM cells is the development of drug resistance. This phenomenon is termed “cell adhesion-mediated drug resistance” (CAM-DR) and it is thought to be one of the major mechanisms by which MM cells escape the cytotoxic effects of therapeutic agents [68]. VLA-4 or α 4 β 1 integrin is a critical molecule for the induction of CAM-DR in MM cells, and it was shown that bortezomib enhances the effects of conventional antimyeloma agents by overcoming VLA-4-mediated CAM-DR, and bortezomib-based combination chemotherapy can improve the treatment outcome of patients with MM [69].…”

Section: Targeting the Bm Microenvironmentmentioning

confidence: 99%

Molecularly Targeted Therapies in Multiple Myeloma

Puente

Muz

Azab

et al. 2014

Leukemia Research and Treatment

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Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

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Cited by 146 publications

References 46 publications

Evidence of a Role for Activation of Wnt/β-Catenin Signaling in the Resistance of Plasma Cells to Lenalidomide

Evidence of a Role for Activation of Wnt/β-Catenin Signaling in the Resistance of Plasma Cells to Lenalidomide

Nanomedicine therapeutic approaches to overcome cancer drug resistance

Molecularly Targeted Therapies in Multiple Myeloma

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