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AuthorMalka, Matthews M.dc.contributor.author
AuthorEberle, Juliadc.contributor.author
AuthorNiedermayer, Kathrindc.contributor.author
AuthorZlotos, Darius P.dc.contributor.author
AuthorWiesmüller, Lisadc.contributor.author
Date of accession2021-11-29T10:10:22Zdc.date.accessioned
Available in OPARU since2021-11-29T10:10:22Zdc.date.available
Date of first publication2021-07-03dc.date.issued
AbstractThe genetic principle of synthetic lethality has most successfully been exploited in therapies engaging Poly-ADP-ribose-polymerase (PARP) inhibitors to treat patients with homologous recombination (HR)-defective tumors. In this work, we went a step further following the idea of a local molecular cooperation and designed hybrid compounds M1–M3. The drug conjugates M1–M3 combine Olaparib, the first PARP inhibitor approved for clinical use, with Cpd 1, an inhibitor of RAD51 that blocks its HR functions and yet permits RAD51 nucleoprotein filament formation on single-stranded DNA. While in M2 and M3, the parental drugs are linked by -CO-(CH2)n-CO-spacers (n = 2 and 4, respectively), they are directly merged omitting the piperazine ring of Olaparib in M1. Monitoring anti-survival effects of M1–M3 in six breast cancer cell lines of different molecular subtypes showed that in each cell line, at least one of the drug conjugates decreased viability by one to two orders of magnitude compared with parental drugs. While triple-negative breast cancer (TNBC) cells with frequent BRCA1 pathway dysfunction were sensitive to spacer-linked hybrid compounds M1 and M2 regardless of their HR capacities, non-TNBC cells were responsive to the merged drug conjugate M1 only, suggesting different spatial requirements for dual inhibition in these two groups of cell lines. These results demonstrate that, depending on chemical linkage, dual PARP1-RAD51 inhibitory drugs can either sensitize non-TNBC and re-sensitize TNBC cells, or discriminate between these groups of cells.dc.description.abstract
Languageendc.language.iso
PublisherUniversität Ulmdc.publisher
LicenseCC BY 4.0 Internationaldc.rights
Link to license texthttps://creativecommons.org/licenses/by/4.0/dc.rights.uri
KeywordPARP inhibitordc.subject
KeywordOlaparibdc.subject
KeywordRAD51 inhibitordc.subject
Keyworddrug conjugatesdc.subject
Keywordanticancer drug hybridsdc.subject
Keywordtriple-negative breast cancerdc.subject
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
MeSHPoly(ADP-ribose) polymerase inhibitorsdc.subject.mesh
MeSHBreast neoplasms; Drug therapydc.subject.mesh
MeSHAntineoplastic agents; Therapeutic usedc.subject.mesh
TitleDual PARP and RAD51 inhibitory drug conjugates show synergistic and selective effects on breast cancer cellsdc.title
Resource typeWissenschaftlicher Artikeldc.type
SWORD Date2021-08-01T11:47:11Zdc.date.updated
VersionpublishedVersiondc.description.version
DOIhttp://dx.doi.org/10.18725/OPARU-40030dc.identifier.doi
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-40106-0dc.identifier.urn
GNDBrustkrebsdc.subject.gnd
GNDCytostatikumdc.subject.gnd
InstitutionUKU. Klinik für Frauenheilkunde und Geburtshilfeuulm.affiliationSpecific
Peer reviewjauulm.peerReview
DCMI TypeTextuulm.typeDCMI
CategoryPublikationenuulm.category
In cooperation withGerman University in Cairouulm.cooperation
DOI of original publication10.3390/biom11070981dc.relation1.doi
Source - Title of sourceBiomoleculessource.title
Source - Place of publicationMDPIsource.publisher
Source - Volume11source.volume
Source - Issue7source.issue
Source - Year2021source.year
Source - Article number981source.articleNumber
Source - eISSN2218-273Xsource.identifier.eissn
Open AccessGreen Published, golduulm.OA
WoS000676794700001uulm.identifier.wos
Bibliographyuulmuulm.bibliographie
DFG project uulmSFB 1279 / Nutzung des menschlichen Peptidoms für die Entwicklung neuer antimikrobieller und anti-Krebs Therapeutika / DFG / 316249678uulm.projectDFG
DFG project uulmGRK 2254 / HEIST / Heterogenität und Evolution in soliden Tumoren (HEIST) / DFG / 288342734uulm.projectDFG


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