Data from Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib
| العنوان: | Data from Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib |
|---|---|
| المؤلفون: | Nicholas Mitsiades, Kenneth C. Anderson, Constantine S. Mitsiades, Paul G. Richardson, Peter O'Gorman, Martin Clynes, Leutz Buon, Teru Hideshima, Dharminder Chauhan, Nikhil C. Munshi, Noopur S. Raje, Emily Daskalaki, Elpida Charalambous, Douglas W. McMillin, Vassiliki Kotoula, Patrick J. Hayden, Melissa G. Ooi |
| بيانات النشر: | American Association for Cancer Research (AACR), 2023. |
| سنة النشر: | 2023 |
| الوصف: | Purpose: p53 is inactivated in many human malignancies through missense mutations or overexpression of the human homologue of Mdm2 (Hdm2), an E3 ubiquitin ligase that ubiquitinates p53, thereby promoting its proteasomal degradation. The cis-imidazoline nutlin-3 can disrupt the p53-Hdm2 interaction and activate p53, inducing apoptosis in vitro in many malignancies, including multiple myeloma (MM).Experimental Design: We hypothesized that suppression of Hdm2-mediated p53 ubiquitination may augment sequelae of p53 accumulation caused by proteasomal inhibition. We compared the response of MM cells versus several epithelial cancer models to the proteasome inhibitor bortezomib in combination with nutlin-3.Results: The combination of sublethal concentrations of bortezomib plus nutlin-3 induced additive cytotoxicity against bortezomib-sensitive MM cell lines. Importantly, however, in breast, prostate, colon, and thyroid (papillary, follicular, anaplastic, and medullary) carcinoma cell lines, this combination triggered synergistic cytotoxicity, and increased expression of p53, p21, Hdm2, Bax, Noxa, PUMA, and cleavage of caspase-3 and poly ADP ribose polymerase. Coculture with bone marrow stromal cells attenuated MM cell sensitivity to nutlin-3 monotherapy and was associated with evidence of suppression of p53 activity in MM cells, whereas combined bortezomib-nutlin-3 treatment maintained cytotoxicity even in the presence of bone marrow stromal cells.Conclusions: This differential response of MM versus epithelial carcinomas to combination of nutlin-3 with bortezomib sheds new light on the role of p53 in bortezomib-induced apoptosis. Concurrent Hdm2 inhibition with bortezomib may extend the spectrum of bortezomib applications to malignancies with currently limited sensitivity to single-agent bortezomib or, in the future, to MM patients with decreased clinical responsiveness to bortezomib-based therapy. (Clin Cancer Res 2009;15(23):7153–60) |
| DOI: | 10.1158/1078-0432.c.6517366.v1 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::728045ed524eeea6ccdefabb43cb52bf https://doi.org/10.1158/1078-0432.c.6517366.v1 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....728045ed524eeea6ccdefabb43cb52bf |
| قاعدة البيانات: | OpenAIRE |
| ResultId |
1 |
|---|---|
| Header |
edsair OpenAIRE edsair.doi.dedup.....728045ed524eeea6ccdefabb43cb52bf 894 3 unknown 894.30615234375 |
| PLink |
https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsair&AN=edsair.doi.dedup.....728045ed524eeea6ccdefabb43cb52bf&custid=s6537998&authtype=sso |
| FullText |
Array
(
[Availability] => 0
)
Array ( [0] => Array ( [Url] => https://explore.openaire.eu/search/publication?articleId=doi_dedup___::728045ed524eeea6ccdefabb43cb52bf# [Name] => EDS - OpenAIRE [Category] => fullText [Text] => View record in OpenAIRE [MouseOverText] => View record in OpenAIRE ) ) |
| Items |
Array
(
[Name] => Title
[Label] => Title
[Group] => Ti
[Data] => Data from Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib
)
Array ( [Name] => Author [Label] => Authors [Group] => Au [Data] => <searchLink fieldCode="AR" term="%22Nicholas+Mitsiades%22">Nicholas Mitsiades</searchLink><br /><searchLink fieldCode="AR" term="%22Kenneth+C%2E+Anderson%22">Kenneth C. Anderson</searchLink><br /><searchLink fieldCode="AR" term="%22Constantine+S%2E+Mitsiades%22">Constantine S. Mitsiades</searchLink><br /><searchLink fieldCode="AR" term="%22Paul+G%2E+Richardson%22">Paul G. Richardson</searchLink><br /><searchLink fieldCode="AR" term="%22Peter+O'Gorman%22">Peter O'Gorman</searchLink><br /><searchLink fieldCode="AR" term="%22Martin+Clynes%22">Martin Clynes</searchLink><br /><searchLink fieldCode="AR" term="%22Leutz+Buon%22">Leutz Buon</searchLink><br /><searchLink fieldCode="AR" term="%22Teru+Hideshima%22">Teru Hideshima</searchLink><br /><searchLink fieldCode="AR" term="%22Dharminder+Chauhan%22">Dharminder Chauhan</searchLink><br /><searchLink fieldCode="AR" term="%22Nikhil+C%2E+Munshi%22">Nikhil C. Munshi</searchLink><br /><searchLink fieldCode="AR" term="%22Noopur+S%2E+Raje%22">Noopur S. Raje</searchLink><br /><searchLink fieldCode="AR" term="%22Emily+Daskalaki%22">Emily Daskalaki</searchLink><br /><searchLink fieldCode="AR" term="%22Elpida+Charalambous%22">Elpida Charalambous</searchLink><br /><searchLink fieldCode="AR" term="%22Douglas+W%2E+McMillin%22">Douglas W. McMillin</searchLink><br /><searchLink fieldCode="AR" term="%22Vassiliki+Kotoula%22">Vassiliki Kotoula</searchLink><br /><searchLink fieldCode="AR" term="%22Patrick+J%2E+Hayden%22">Patrick J. Hayden</searchLink><br /><searchLink fieldCode="AR" term="%22Melissa+G%2E+Ooi%22">Melissa G. Ooi</searchLink> ) Array ( [Name] => Publisher [Label] => Publisher Information [Group] => PubInfo [Data] => American Association for Cancer Research (AACR), 2023. ) Array ( [Name] => DatePubCY [Label] => Publication Year [Group] => Date [Data] => 2023 ) Array ( [Name] => Abstract [Label] => Description [Group] => Ab [Data] => Purpose: p53 is inactivated in many human malignancies through missense mutations or overexpression of the human homologue of Mdm2 (Hdm2), an E3 ubiquitin ligase that ubiquitinates p53, thereby promoting its proteasomal degradation. The cis-imidazoline nutlin-3 can disrupt the p53-Hdm2 interaction and activate p53, inducing apoptosis in vitro in many malignancies, including multiple myeloma (MM).Experimental Design: We hypothesized that suppression of Hdm2-mediated p53 ubiquitination may augment sequelae of p53 accumulation caused by proteasomal inhibition. We compared the response of MM cells versus several epithelial cancer models to the proteasome inhibitor bortezomib in combination with nutlin-3.Results: The combination of sublethal concentrations of bortezomib plus nutlin-3 induced additive cytotoxicity against bortezomib-sensitive MM cell lines. Importantly, however, in breast, prostate, colon, and thyroid (papillary, follicular, anaplastic, and medullary) carcinoma cell lines, this combination triggered synergistic cytotoxicity, and increased expression of p53, p21, Hdm2, Bax, Noxa, PUMA, and cleavage of caspase-3 and poly ADP ribose polymerase. Coculture with bone marrow stromal cells attenuated MM cell sensitivity to nutlin-3 monotherapy and was associated with evidence of suppression of p53 activity in MM cells, whereas combined bortezomib-nutlin-3 treatment maintained cytotoxicity even in the presence of bone marrow stromal cells.Conclusions: This differential response of MM versus epithelial carcinomas to combination of nutlin-3 with bortezomib sheds new light on the role of p53 in bortezomib-induced apoptosis. Concurrent Hdm2 inhibition with bortezomib may extend the spectrum of bortezomib applications to malignancies with currently limited sensitivity to single-agent bortezomib or, in the future, to MM patients with decreased clinical responsiveness to bortezomib-based therapy. (Clin Cancer Res 2009;15(23):7153–60) ) Array ( [Name] => DOI [Label] => DOI [Group] => ID [Data] => 10.1158/1078-0432.c.6517366.v1 ) Array ( [Name] => URL [Label] => Access URL [Group] => URL [Data] => <link linkTarget="URL" linkTerm="https://explore.openaire.eu/search/publication?articleId=doi_dedup___::728045ed524eeea6ccdefabb43cb52bf" linkWindow="_blank">https://explore.openaire.eu/search/publication?articleId=doi_dedup___::728045ed524eeea6ccdefabb43cb52bf</link><br /><link linkTarget="URL" linkTerm="https://doi.org/10.1158/1078-0432.c.6517366.v1" linkWindow="_blank">https://doi.org/10.1158/1078-0432.c.6517366.v1</link> ) Array ( [Name] => Copyright [Label] => Rights [Group] => Cpyrght [Data] => OPEN ) Array ( [Name] => AN [Label] => Accession Number [Group] => ID [Data] => edsair.doi.dedup.....728045ed524eeea6ccdefabb43cb52bf ) |
| RecordInfo |
Array
(
[BibEntity] => Array
(
[Identifiers] => Array
(
[0] => Array
(
[Type] => doi
[Value] => 10.1158/1078-0432.c.6517366.v1
)
)
[Languages] => Array
(
[0] => Array
(
[Text] => Undetermined
)
)
[Titles] => Array
(
[0] => Array
(
[TitleFull] => Data from Interactions of the Hdm2/p53 and Proteasome Pathways May Enhance the Antitumor Activity of Bortezomib
[Type] => main
)
)
)
[BibRelationships] => Array
(
[HasContributorRelationships] => Array
(
[0] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Nicholas Mitsiades
)
)
)
[1] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Kenneth C. Anderson
)
)
)
[2] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Constantine S. Mitsiades
)
)
)
[3] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Paul G. Richardson
)
)
)
[4] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Peter O'Gorman
)
)
)
[5] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Martin Clynes
)
)
)
[6] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Leutz Buon
)
)
)
[7] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Teru Hideshima
)
)
)
[8] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Dharminder Chauhan
)
)
)
[9] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Nikhil C. Munshi
)
)
)
[10] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Noopur S. Raje
)
)
)
[11] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Emily Daskalaki
)
)
)
[12] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Elpida Charalambous
)
)
)
[13] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Douglas W. McMillin
)
)
)
[14] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Vassiliki Kotoula
)
)
)
[15] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Patrick J. Hayden
)
)
)
[16] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Melissa G. Ooi
)
)
)
)
[IsPartOfRelationships] => Array
(
[0] => Array
(
[BibEntity] => Array
(
[Dates] => Array
(
[0] => Array
(
[D] => 31
[M] => 03
[Type] => published
[Y] => 2023
)
)
[Identifiers] => Array
(
[0] => Array
(
[Type] => issn-locals
[Value] => edsair
)
[1] => Array
(
[Type] => issn-locals
[Value] => edsairFT
)
)
)
)
)
)
)
|
| IllustrationInfo |