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Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer

Although ovarian cancer is a rare disease, it constitutes the fifth leading cause of cancer death among women. It is of major importance to develop new therapeutic strategies to improve survival. Combining P8-D6, a novel dual topoisomerase inhibitor with exceptional anti-tumoral properties in ovaria...

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Autores principales: Flörkemeier, Inken, Hillmann, Julia S., Weimer, Jörg P., Hildebrandt, Jonas, Hedemann, Nina, Rogmans, Christoph, Dempfle, Astrid, Arnold, Norbert, Clement, Bernd, Bauerschlag, Dirk O.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9505822/
https://www.ncbi.nlm.nih.gov/pubmed/36142413
http://dx.doi.org/10.3390/ijms231810503
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author Flörkemeier, Inken
Hillmann, Julia S.
Weimer, Jörg P.
Hildebrandt, Jonas
Hedemann, Nina
Rogmans, Christoph
Dempfle, Astrid
Arnold, Norbert
Clement, Bernd
Bauerschlag, Dirk O.
author_facet Flörkemeier, Inken
Hillmann, Julia S.
Weimer, Jörg P.
Hildebrandt, Jonas
Hedemann, Nina
Rogmans, Christoph
Dempfle, Astrid
Arnold, Norbert
Clement, Bernd
Bauerschlag, Dirk O.
author_sort Flörkemeier, Inken
collection PubMed
description Although ovarian cancer is a rare disease, it constitutes the fifth leading cause of cancer death among women. It is of major importance to develop new therapeutic strategies to improve survival. Combining P8-D6, a novel dual topoisomerase inhibitor with exceptional anti-tumoral properties in ovarian cancer and compounds in preclinical research, and olaparib, a PARP inhibitor targeting DNA damage repair, is a promising approach. P8-D6 induces DNA damage that can be repaired by base excision repair or homologous recombination in which PARP plays a major role. This study analyzed benefits of combining P8-D6 and olaparib treatment in 2D and 3D cultures with ovarian cancer cells. Measurement of viability, cytotoxicity and caspase activity were used to assess therapy efficacy and to calculate the combination index (CI). Further DNA damage was quantified using the biomarkers RAD51 and γH2A.X. The combinational treatment led to an increased caspase activity and reduced viability. CI values partially show synergisms in combinations at 100 nM and 500 nM P8-D6. More DNA damage accumulated, and spheroids lost their membrane integrity due to the combinational treatment. While maintaining the same therapy efficacy as single-drug therapy, doses of P8-D6 and olaparib can be reduced in combinational treatments. Synergisms can be seen in some tested combinations. In summary, the combination therapy indicates benefits and acts synergistic at 100 nM and 500 nM P8-D6.
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spelling pubmed-95058222022-09-24 Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer Flörkemeier, Inken Hillmann, Julia S. Weimer, Jörg P. Hildebrandt, Jonas Hedemann, Nina Rogmans, Christoph Dempfle, Astrid Arnold, Norbert Clement, Bernd Bauerschlag, Dirk O. Int J Mol Sci Article Although ovarian cancer is a rare disease, it constitutes the fifth leading cause of cancer death among women. It is of major importance to develop new therapeutic strategies to improve survival. Combining P8-D6, a novel dual topoisomerase inhibitor with exceptional anti-tumoral properties in ovarian cancer and compounds in preclinical research, and olaparib, a PARP inhibitor targeting DNA damage repair, is a promising approach. P8-D6 induces DNA damage that can be repaired by base excision repair or homologous recombination in which PARP plays a major role. This study analyzed benefits of combining P8-D6 and olaparib treatment in 2D and 3D cultures with ovarian cancer cells. Measurement of viability, cytotoxicity and caspase activity were used to assess therapy efficacy and to calculate the combination index (CI). Further DNA damage was quantified using the biomarkers RAD51 and γH2A.X. The combinational treatment led to an increased caspase activity and reduced viability. CI values partially show synergisms in combinations at 100 nM and 500 nM P8-D6. More DNA damage accumulated, and spheroids lost their membrane integrity due to the combinational treatment. While maintaining the same therapy efficacy as single-drug therapy, doses of P8-D6 and olaparib can be reduced in combinational treatments. Synergisms can be seen in some tested combinations. In summary, the combination therapy indicates benefits and acts synergistic at 100 nM and 500 nM P8-D6. MDPI 2022-09-10 /pmc/articles/PMC9505822/ /pubmed/36142413 http://dx.doi.org/10.3390/ijms231810503 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Flörkemeier, Inken
Hillmann, Julia S.
Weimer, Jörg P.
Hildebrandt, Jonas
Hedemann, Nina
Rogmans, Christoph
Dempfle, Astrid
Arnold, Norbert
Clement, Bernd
Bauerschlag, Dirk O.
Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer
title Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer
title_full Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer
title_fullStr Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer
title_full_unstemmed Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer
title_short Combined PARP and Dual Topoisomerase Inhibition Potentiates Genome Instability and Cell Death in Ovarian Cancer
title_sort combined parp and dual topoisomerase inhibition potentiates genome instability and cell death in ovarian cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9505822/
https://www.ncbi.nlm.nih.gov/pubmed/36142413
http://dx.doi.org/10.3390/ijms231810503
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