Anthelmintic pyrvinium pamoate blocks Wnt/β-catenin and induces apoptosis in multiple myeloma cells

Xu, Fang; Zhu, Yingjie; Lu, Yuhong; Yu, Zhi; Zhong, Jun; Li, Yangqiu; Pan, Jingxuan

doi:10.3892/ol.2018.8006

Cited by 14 publications

(14 citation statements)

References 33 publications

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“…Treatment of both the HMCL RPMI-8226 as well as primary MM cells with PP resulted in an increase in apoptosis. Combinatorial treatment with Bortezomib was also reported in this study to result in a synergistic effect on MM cell viability [ 142 ]. Although the results of these and many other studies are hopeful, challenges for moving these drugs towards treatment of MM lie ahead.…”

Section: The Wnt Pathway As a Potential Therapeutic Target In Multiplsupporting

confidence: 54%

Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential

et al. 2018

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Multiple myeloma is the second most frequent hematological malignancy in the western world and remains incurable, predominantly due to acquired drug resistance and disease relapse. The highly conserved Wnt signal transduction pathway, which plays a key role in regulating cellular processes of proliferation, differentiation, migration, and stem cell self-renewal, is associated with multiple aspects of disease. Bone homeostasis is severely disturbed by Wnt antagonists that are secreted by the malignant plasma cells in the bone marrow. In the vast majority of patients, this results in osteolytic bone disease, which is associated with bone pain and pathological fractures and was reported to facilitate disease progression. More recently, cumulative evidence also indicates the importance of intrinsic Wnt signaling in the survival of multiple myeloma cells. However, Wnt pathway-activating gene mutations could not be identified. The search for factors or processes responsible for Wnt pathway activation currently focuses on aberrant ligand levels in the bone marrow microenvironment, increased expression of Wnt transcriptional co-factors and associated micro-RNAs, and disturbed epigenetics and post-translational modification processes. Furthermore, Wnt pathway activation is associated with acquired cell adhesion-mediated resistance of multiple myeloma cells to conventional drug therapies, including doxorubicin and lenalidomide. In this review, we present an overview of the relevance of Wnt signaling in multiple myeloma and highlight the Wnt pathway as a potential therapeutic target for this disease.

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Section: The Wnt Pathway As a Potential Therapeutic Target In Multiplsupporting

confidence: 54%

Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential

et al. 2018

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“…Moreover, inhibition of Wnt signaling by ectopic expression of a dominant negative TCF4 mutant (dnTCF4) in HMCLs suppressed proliferation, implying functional involvement of β-catenin/TCF-mediated transcription. Corroborating these results, other studies showed that siRNA [33] and shRNA [34] mediated silencing of β-catenin or treatment of HMCLs with the small molecule Wnt/β-catenin inhibitors PKF115-584 [35], AV-65 [36], BC2059 [37], CGK012 [38], and the FDA-approved Pyrvinium pamoate [39, 40] attenuated cell cycle progression, impaired tumor growth, and markedly increased apoptosis of HMCLs both in vitro and in vivo. In addition to attenuating proliferation, silencing of β-catenin increased the sensitivity of the tumor cells to multiple drugs used in the treatment of MM, in particular to lenalidomide [34, 41].…”

Section: Aberrant Canonical Wnt Signaling In MM Cellsmentioning

confidence: 89%

Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options

et al. 2019

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Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.

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“…First, pyrvinium inhibits canonical Wnt signaling pathway by β-catenin degradation in multiple myeloma. Secondly, pyrvinium impairs mitochondrial functions in multiple hematological malignancies [14 , [22] , [23] , [24] , [25] . Here, we investigated both possible mechanisms to identify how pyrvinium exerts its anti-leukemic effects in AML cells.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have described two mechanisms by which pyrvinium exerts its anti-neoplastic effects. Pyrvinium is able to inhibit the canonical Wnt signaling pathway via β-catenin degradation, but can also impair mitochondrial respiration [14 , [22] , [23] , [24] , [25] . As our data showed a lack of β-catenin expression in MLL -rearranged AML cells, it is unlikely that pyrvinium affected Wnt signaling in these cells.…”

Section: Discussionmentioning

confidence: 99%

High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia

Wander

Arentsen-Peters

Pinhanҫos

et al. 2021

Translational Oncology

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Highlights Drug library screening identified pyrvinium to be effective against MLL -rearranged AML. Pyrvinium targets the mitochondria of MLL -rearranged AML cells. Pyrvinium does not antagonize with standard chemotherapy in MLL -rearranged AML.

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Anthelmintic pyrvinium pamoate blocks Wnt/β-catenin and induces apoptosis in multiple myeloma cells

Cited by 14 publications

References 33 publications

Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential

Wnt signaling in multiple myeloma: a central player in disease with therapeutic potential

Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options

High-throughput drug screening reveals Pyrvinium pamoate as effective candidate against pediatric MLL-rearranged acute myeloid leukemia

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