Targeting the proteasome as a promising therapeutic strategy in thyroid cancer

Wunderlich, Annette; Arndt, Tjadina; Fischer, M.; Roth, Silvia; Ramaswamy, Annette; Greene, Brandon; Brendel, Cornelia; Hinterseher, Ulrike; Bartsch, Detlef K.; Hoffmann, Sebastian

doi:10.1002/jso.22113

Cited by 14 publications

(8 citation statements)

References 44 publications

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“…Bortezomib, the first inhibitor of the UPP to be used in clinical studies, has been extensively studied for both hematological and solid cancers, including thyroid cancer (Hideshima et al 2001, Papandreou et al 2004, Mitsiades et al 2006, Altmann et al 2012, Wunderlich et al 2012. Results of recent preclinical studies have also indicated that bortezomib inhibits ATC cell proliferation and induces caspase-dependent apoptosis in vitro, with potent antitumor effects in vivo as well (Mitsiades et al 2006, Conticello et al 2007, Altmann et al 2012, Wunderlich et al 2012.…”

Section: Discussionmentioning

confidence: 99%

“…Results of recent preclinical studies have also indicated that bortezomib inhibits ATC cell proliferation and induces caspase-dependent apoptosis in vitro, with potent antitumor effects in vivo as well (Mitsiades et al 2006, Conticello et al 2007, Altmann et al 2012, Wunderlich et al 2012. The clinical efficacy of bortezomib, however, is challenged by the rapid development of drug resistance, as it is not an irreversible proteasome inhibitor like carfilzomib, and also by the dose-limiting neurotoxicity associated with bortezomib treatment (Ruckrich et al 2009, Jain et al 2011.…”

Section: Discussionmentioning

confidence: 99%

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Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer

Mehta¹,

Zhang²,

Boufraqech³

et al. 2015

Endocrine-Related Cancer

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Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies. Currently, there is no standard or effective therapy for ATC. Drug repurposing for cancer treatment is an emerging approach for identifying compounds that may have antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines. Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three proteasome inhibitors screened, a second-generation proteasome inhibitor, carfilzomib, was the most active. Treatment of ATC cells with carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically, carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the anti-apoptotic protein ATF4. Pretreatment with carfilzomib reduced in vivo metastases (lung, bone, liver, and kidney) and disease progression, and decreased N-cadherin expression. Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer

Mehta¹,

Zhang²,

Boufraqech³

et al. 2015

Endocrine-Related Cancer

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“…It is possible to interfere with NF-κB activation at different levels, targeting components of its signaling cascade such as the IKK complex, the IκBα inhibitory protein, the proteasome, and the RelA subunit of the transcriptionally active heterodimers. It has been reported that the anti-apoptotic behavior and invasiveness of TC cells transformed by oncogenic BRAF involved NF-κB activation [20,21]. …”

Section: Introductionmentioning

confidence: 99%

Simultaneous suppression of the MAP kinase and NF-κB pathways provides a robust therapeutic potential for thyroid cancer

et al. 2015

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The MAP kinase and NF-κB signaling pathways play an important role in thyroid cancer tumorigenesis. We aimed to examine the therapeutic potential of dually targeting the two pathways using AZD6244 and Bortezomib in combination. We evaluated their effects on cell proliferation, cell-cycle progression, apoptosis, cell migration assay, and the activation of the MAPK pathway in vitro and the in vivo using tumor size and immunohistochemical changes of Ki67 and ppRB. We found inhibition of cell growth rate by 10%, 20%, and 56% (p < 0.05), migration to 55%, 61%, and 29% (p < 0.05), and induction of apoptosis to 10%, 15%, and 38% (p < 0.05) with AZD6244, Bortezomib, or combination, respectively. Induction of cell cycle arrest occurred only with drug combination. Dual drug treatment in the xenograft model caused a 94% reduction in tumor size (p < 0.05) versus 15% with AZD6244 and 34% with Bortezomib (p < 0.05) and also reduced proliferative marker Ki67, and increased pRb dephosphorylation. Our results demonstrate a robust therapeutic potential of combining AZD6244 and Bortezomib as an effective strategy to overcome drug resistance encountered in monotherapy in the treatment of thyroid cancer, strongly supporting clinical trials to further test this strategy.

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“…Long tested for its anti cancer properties in multiple myeloma, it was approved by FDA for treatment of patients with multiple myeloma [16,17]. Bortezomib has also been shown to exert anti-cancer activity against many cancer types [18,19]. More recently compounds with irreversible mode of action are considered to be the second generation of proteasome inhibitors and have shown promising results in clinical trials namely Carfilzomib (PR-171), Salinosporamide A (NP-0052) and MLN9708 [20,21].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic targeting of cancer cell cycle using proteasome inhibitors

Rastogi

Mishra

2012

Cell Div

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Proteasomes are multicatalytic protease complexes in the cell, involved in the non-lysosomal recycling of intra-cellular proteins. Proteasomes play a critical role in regulation of cell division in both normal as well as cancer cells. In cancer cells this homeostatic function is deregulated leading to the hyperactivation of the proteasomes. Proteasome inhibitors (PIs) are a class of compounds, which either reversibly or irreversibly block the activity of proteasomes and induce cancer cell death. Interference of PIs with the ubiquitin proteasome pathway (UPP) involved in protein turnover in the cell leads to the accumulation of proteins engaged in cell cycle progression, which ultimately put a halt to cancer cell division and induce apoptosis. Upregulation of many tumor suppressor proteins involved in cell cycle arrest are known to play a role in PI induced cell cycle arrest in a variety of cancer cells. Although many PIs target the proteasomes, not all of them are effective in cancer therapy. Some cancers develop resistance against proteasome inhibition by possibly activating compensatory signaling pathways. However, the details of the activation of these pathways and their contribution to resistance to PI therapy remain obscure. Delineation of these pathways may help in checking resistance against PIs and deducing effective combinational approaches for improved treatment strategies. This review will discuss some of the signaling pathways related to proteasome inhibition and cell division that may help explain the basis of resistance of some cancers to proteasome inhibitors and underline the need for usage of PIs in combination with traditional chemotherapy.

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Targeting the proteasome as a promising therapeutic strategy in thyroid cancer

Abstract: Proteasome inhibition is effective in reducing cell growth and inducing apoptosis of ATC in vitro and inhibiting tumor growth and vascularity in vivo. However, the impact on nuclear transcription remains controversial. Clinical evaluation of bortezomib treatment in ATC is warranted.

Cited by 14 publications

References 44 publications

Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer

Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer

Simultaneous suppression of the MAP kinase and NF-κB pathways provides a robust therapeutic potential for thyroid cancer

Therapeutic targeting of cancer cell cycle using proteasome inhibitors

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