RETRACTED: Antitumor activity of bortezomib in human cancer cells with acquired resistance to anti-epidermal growth factor receptor tyrosine kinase inhibitors

Morgillo, Floriana; D’Aiuto, Elena; Troiani, Teresa; Martinelli, Erika; Cascone, Tina; Palma, Raffaele De; Orditura, Michele; Vita, Ferdinando De; Ciardiello, Fortunato

doi:10.1016/j.lungcan.2010.06.005

Cited by 32 publications

(33 citation statements)

References 36 publications

(51 reference statements)

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“…Malignant cells generally have higher protein synthesis rates than their normal counterparts, making them more prone to protein aggregation and perhaps more sensitive to proteasome inhibitor-induced apoptosis. Inhibition of proteasome activity has been demonstrated to induce proapoptotic ER stress in pancreatic carcinoma (25), head and neck cancer (26), and nonsmall cell lung carcinoma (27).…”

Section: Discussionmentioning

confidence: 99%

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Hideshima

Paranal

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

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Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro. However, these foundational studies were limited by the pharmacologic liabilities of tubacin as a chemical probe with only in vitro utility.Emerging from a focused library synthesis, a potent, selective, and bioavailable HDAC6 inhibitor, WT161, was created to study the mechanism of action of HDAC6 inhibition in MM alone and in combination with BTZ. WT161 in combination with BTZ triggers significant accumulation of polyubiquitinated proteins and cell stress, followed by caspase activation and apoptosis. More importantly, this combination treatment was effective in BTZ-resistant cells and in the presence of bone marrow stromal cells, which have been shown to mediate MM cell drug resistance. The activity of WT161 was confirmed in our human MM cell xenograft mouse model and established the framework for clinical trials of the combination treatment to improve patient outcomes in MM.histone deacetylase 6 | proteasome inhibitor | multiple myeloma | bortezomib-resistance | WT161

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Section: Discussionmentioning

confidence: 99%

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Hideshima

Paranal

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

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“…Not surprisingly, inhibition of the proteasome resulted in UPR-associated cell death in several cell lines [104][105][106][107][108][109][110]. Interestingly, involvement of UPR in apoptosis has also been reported in cells treated with a PyDTC-Cu(II) [27] or disulfiram-Cu(II) mixture [111] and other copper compounds [111][112][113].…”

Section: Becausementioning

confidence: 92%

Diethyldithiocarbamate complex with copper: the mechanism of action in cancer cells

Škrott

Cvek²

2012

MRMC

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The idea of "repurposing" of existing drugs provides an effective way to develop and identify new therapies. Disulfiram (Antabuse), a drug commonly used for the treatment of alcoholism, shows promising anticancer activity in both preclinical and clinical studies. In the human body, disulfiram is rapidly converted to its reduced metabolite, diethyldithiocarbamate. If copper ions are available, a bis(diethyldithiocarbamate)-copper(II) complex is formed. Disulfiram's selective anticancer activity is attributed to the copper(II) complex's ability to inhibit the cellular proteasome. It is assumed that the complex inhibits the proteasome by a mechanism that is distinct to the clinically used drug bortezomib, targeting the 19S rather than the 20S proteasome. This difference could be explained by inhibition of the JAMM domain of the POH1 subunit within the lid of the 19S proteasome.

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“…Support for this is provided by studies in which AKT activity was de-coupled from upstream PI3K; treatment with gefitinib did not effect cell death when AKT was activated via tensin homolog (PTEN) down-regulation (Bianco et al, 2003;She et al, 2003;Yamamoto et al, 2010). Furthermore, Morgillo and colleagues showed that levels of pAKT were increased in Calu-3 cell lines with acquired resistance to either erlotinib or gefitinib (Morgillo et al, 2010). Cisplatin resistance has been frequently associated with an activation of the PI3K and AKT pathway in ovarian cancer (Lee et al, 2005b;Yang et al, 2006) and NSCLC cancer cells (Chin et al, 2008).…”

Section: The Egfr-tki Resistant Phenotypementioning

confidence: 99%

“…Alternating treatment between erlotinib and gefitinib may not prove adequate, as crossresistance studies on NSCLC-derived Calu-3 cell lines have shown (Morgillo et al, 2010). The erlotinib-resistant cell line was resistant to gefitinib and vice versa due to similar mechanisms of resistance.…”

Section: Other Tki Therapeutic Strategies For Platinum-resistant Cancersmentioning

confidence: 99%

Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer: A systematic review

Murphy

Stordal

2011

Drug Resistance Updates

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Copyright and moral rights to this thesis/research project are retained by the author and/or other copyright owners. The work is supplied on the understanding that any use for commercial gain is strictly forbidden. A copy may be downloaded for personal, non-commercial, research or study without prior permission and without charge. Any use of the thesis/research project for private study or research must be properly acknowledged with reference to the work's full bibliographic details.This thesis/research project may not be reproduced in any format or medium, or extensive quotations taken from it, or its content changed in any way, without first obtaining permission in writing from the copyright holder(s).If you believe that any material held in the repository infringes copyright law, please contact the Repository Team at Middlesex University via the following email address:The item will be removed from the repository while any claim is being investigated. Methods: A systematic review was conducted to investigate whether two EGFR-TKIs, erlotinib and gefitinib, have efficacy in the platinum-resistance setting. Preclinical studies of platinum-resistant cancer cell lines, which had been subsequently treated with EGFRTKIs, were sought to establish proof-of-concept. Clinical trials reporting administration of EGFR-TKIs to ovarian cancer and NSCLC patients relapsed after therapy with platinum drugs were investigated to determine sensitivity of these cohorts to EGFR-TKI treatment. The role of EGFR mutation, copy number and protein expression on response to EGFR-TKIs after failure of platinum chemotherapy were also investigated.Results: Preclinical models of platinum-resistant cancer were found which display a spectrum of cross-resistance profiles to EGFR-TKIs. Sensitivity to EGFR-TKIs is dependent on the activation of the EGFR pathway or EGFR interacting proteins such as HER-2. EGFR-TKIs show favourable response rates in platinum-pretreated NSCLC, 11.14% and 15.25% for 150 mg/day erlotinib and 250 mg/day gefitinib, respectively. These response rates significantly improve in patients of Asian descent (28.3% and 29.17%, respectively) and patients with EGFR activation mutations (41.6% and 63.89%, respectively) or increased copy number (33.3% and 45.45%, respectively). Gefitinib significantly outperformed erlotinib and should therefore be the EGFR-TKI of choice in platinum-pretreated relapsed NSCLC. In contrast, response rates are very poor to both erlotinib and gefitinib in platinum pretreated ovarian cancer, 0-5.9% and they should not be used in this cohort of patients.Preclinical models demonstrate that, while cross resistance can occur between platinums and EGFR-TKIs, there is not a generalised cross-resistance phenotype. Erlotinib and gefitinib are suitable for the treatment of platinum-pretreated NSCLC, particularly in patients with EGFR mutations or increases in copy number. Unfortunately, the high rates of EGFR protein overexpression in ovarian cancer are not translating to a clinically useful therapeutic target for ...

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RETRACTED: Antitumor activity of bortezomib in human cancer cells with acquired resistance to anti-epidermal growth factor receptor tyrosine kinase inhibitors

Cited by 32 publications

References 36 publications

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Discovery of selective small-molecule HDAC6 inhibitor for overcoming proteasome inhibitor resistance in multiple myeloma

Diethyldithiocarbamate complex with copper: the mechanism of action in cancer cells

Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer: A systematic review

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