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dc.contributor.author
Qin, Yun
dc.contributor.author
Imobersteg, Stefan
dc.contributor.author
Frank, Stephan
dc.contributor.author
Blanc, Alain
dc.contributor.author
Chiorazzo, Tanja
dc.contributor.author
Berger, Philipp
dc.contributor.author
Schibli, Roger
dc.contributor.author
Béhé, Martin P.
dc.contributor.author
Grzmil, Michal
dc.date.accessioned
2023-06-12T13:44:23Z
dc.date.available
2023-06-12T03:14:59Z
dc.date.available
2023-06-12T13:44:23Z
dc.date.issued
2023-06-01
dc.identifier.issn
0097-9058
dc.identifier.issn
0022-3123
dc.identifier.issn
0161-5505
dc.identifier.issn
2159-662X
dc.identifier.issn
1535-5667
dc.identifier.other
10.2967/jnumed.122.264597
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/616056
dc.identifier.doi
10.3929/ethz-b-000616056
dc.description.abstract
α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of targeted α-particle therapy (TAT). Identification of the radiation-activated mechanisms that drive cancer cell survival provides opportunities to develop new points for therapeutic interference to improve the efficacy and safety of TAT. Methods: Quantitative phosphoproteomics and matching proteomics followed by the bioinformatics analysis were used to identify alterations in the signaling networks in response to TAT with the 225Ac-labeled minigastrin analog 225Ac-PP-F11N (DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) in A431 cells, which overexpress cholecystokinin B receptor (CCKBR). Western blot analysis and microscopy verified the activation of the selected signaling pathways. Small-molecule inhibitors were used to validate the potential of the radiosensitizing combinatory treatments both in vitro and in A431/CCKBR tumor-bearing nude mice. Results: TAT-induced alterations were involved in DNA damage response, cell cycle regulation, and signal transduction, as well as RNA transcription and processing, cell morphology, and transport. Western blot analysis and microscopy confirmed increased phosphorylations of the key proteins involved in DNA damage response and carcinogenesis, including p53, p53 binding protein 1 (p53BP1), histone deacetylases (HDACs), and H2AX. Inhibition of HDAC class II, ataxia-telangiectasia mutated (ATM), and p38 kinases by TMP269, AZD1390, and SB202190, respectively, sensitized A431/CCKBR cells to 225Ac-PP-F11N. As compared with the control and monotherapies, the combination of 225Ac-PP-F11N with the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) significantly reduced the viability and increased the DNA damage of A431/CCKBR cells, led to the most pronounced tumor growth inhibition, and extended the mean survival of A431/CCKBR xenografted nude mice. Conclusion: Our study revealed the cellular responses to TAT and demonstrated the radiosensitizing potential of HDAC inhibitors to 225Ac-PP-F11N in CCKBR-positive tumors. This proof-of-concept study recommends development of novel radiosensitizing strategies by targeting TAT-activated and survival-promoting signaling pathways.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Society of Nuclear Medicine
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.subject
225Ac
en_US
dc.subject
phosphoproteomics
en_US
dc.subject
minigastrin
en_US
dc.subject
CCKBR
en_US
dc.subject
radioresistance
en_US
dc.title
Signaling Network Response to α-Particle–Targeted Therapy with the 225Ac-Labeled Minigastrin Analog 225Ac-PP-F11N Reveals the Radiosensitizing Potential of Histone Deacetylase Inhibitors
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2023-02-02
ethz.journal.title
The Journal of Nuclear Medicine
ethz.journal.volume
64
en_US
ethz.journal.issue
6
en_US
ethz.journal.abbreviated
J Nucl Med
ethz.pages.start
873
en_US
ethz.pages.end
879
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Reston, VA
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03688 - Schibli, Roger / Schibli, Roger
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03688 - Schibli, Roger / Schibli, Roger
ethz.date.deposited
2023-06-12T03:15:01Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2023-06-12T13:44:24Z
ethz.rosetta.lastUpdated
2024-02-03T00:04:00Z
ethz.rosetta.versionExported
true
ethz.COinS
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