PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells
PARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the com...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-05-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphys.2019.00538/full |
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| author | Anna Maria Cseh Anna Maria Cseh Zsolt Fabian Ruben Quintana-Cabrera Ruben Quintana-Cabrera Ruben Quintana-Cabrera Aliz Szabo Aliz Szabo Krisztian Eros Krisztian Eros Krisztian Eros Maria Eugenia Soriano Maria Eugenia Soriano Ferenc Gallyas Ferenc Gallyas Ferenc Gallyas Luca Scorrano Luca Scorrano Balazs Sumegi Balazs Sumegi Balazs Sumegi |
| author_facet | Anna Maria Cseh Anna Maria Cseh Zsolt Fabian Ruben Quintana-Cabrera Ruben Quintana-Cabrera Ruben Quintana-Cabrera Aliz Szabo Aliz Szabo Krisztian Eros Krisztian Eros Krisztian Eros Maria Eugenia Soriano Maria Eugenia Soriano Ferenc Gallyas Ferenc Gallyas Ferenc Gallyas Luca Scorrano Luca Scorrano Balazs Sumegi Balazs Sumegi Balazs Sumegi |
| author_sort | Anna Maria Cseh |
| collection | DOAJ |
| description | PARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities. |
| first_indexed | 2024-12-10T11:44:58Z |
| format | Article |
| id | doaj.art-f381065919764ca58bfa19b4e21df72f |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-10T11:44:58Z |
| publishDate | 2019-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-f381065919764ca58bfa19b4e21df72f2022-12-22T01:50:07ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2019-05-011010.3389/fphys.2019.00538450637PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma CellsAnna Maria Cseh0Anna Maria Cseh1Zsolt Fabian2Ruben Quintana-Cabrera3Ruben Quintana-Cabrera4Ruben Quintana-Cabrera5Aliz Szabo6Aliz Szabo7Krisztian Eros8Krisztian Eros9Krisztian Eros10Maria Eugenia Soriano11Maria Eugenia Soriano12Ferenc Gallyas13Ferenc Gallyas14Ferenc Gallyas15Luca Scorrano16Luca Scorrano17Balazs Sumegi18Balazs Sumegi19Balazs Sumegi20Department of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, HungaryDepartment of Biology, University of Padova, Padua, ItalyDepartment of Medical Chemistry, Molecular Biology and Pathobiochemistry, Faculty of Medicine, Semmelweis University, Budapest, HungaryInstitute of Functional Biology and Genomics, University of Salamanca, Consejo Superior de Investigaciones Científicas, Salamanca, SpainInstitute of Biomedical Research of Salamanca, University Hospital of Salamanca, University of Salamanca, Consejo Superior de Investigaciones Científicas, Salamanca, SpainCIBERFES, Instituto de Salud Carlos III, Madrid, SpainDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, HungaryNuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences, Budapest, HungaryDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, HungaryNuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences, Budapest, HungarySzentagothai Research Centre, University of Pécs, Pécs, HungaryDepartment of Biology, University of Padova, Padua, ItalyVenetian Institute of Molecular Medicine, Padua, ItalyDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, HungaryNuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences, Budapest, HungarySzentagothai Research Centre, University of Pécs, Pécs, HungaryDepartment of Biology, University of Padova, Padua, ItalyVenetian Institute of Molecular Medicine, Padua, ItalyDepartment of Biochemistry and Medical Chemistry, Medical School, University of Pécs, Pécs, HungaryNuclear-Mitochondrial Interactions Research Group, Hungarian Academy of Sciences, Budapest, HungarySzentagothai Research Centre, University of Pécs, Pécs, HungaryPARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities.https://www.frontiersin.org/article/10.3389/fphys.2019.00538/fullPARPmitochondriacancermelanomacell death |
| spellingShingle | Anna Maria Cseh Anna Maria Cseh Zsolt Fabian Ruben Quintana-Cabrera Ruben Quintana-Cabrera Ruben Quintana-Cabrera Aliz Szabo Aliz Szabo Krisztian Eros Krisztian Eros Krisztian Eros Maria Eugenia Soriano Maria Eugenia Soriano Ferenc Gallyas Ferenc Gallyas Ferenc Gallyas Luca Scorrano Luca Scorrano Balazs Sumegi Balazs Sumegi Balazs Sumegi PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells Frontiers in Physiology PARP mitochondria cancer melanoma cell death |
| title | PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells |
| title_full | PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells |
| title_fullStr | PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells |
| title_full_unstemmed | PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells |
| title_short | PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells |
| title_sort | parp inhibitor pj34 protects mitochondria and induces dna damage mediated apoptosis in combination with cisplatin or temozolomide in b16f10 melanoma cells |
| topic | PARP mitochondria cancer melanoma cell death |
| url | https://www.frontiersin.org/article/10.3389/fphys.2019.00538/full |
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