Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells
The 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 coo...
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| Format: | Article |
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MDPI AG
2021-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/11/7/981 |
| _version_ | 1797527567486418944 |
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| author | Matthews M. Malka Julia Eberle Kathrin Niedermayer Darius P. Zlotos Lisa Wiesmüller |
| author_facet | Matthews M. Malka Julia Eberle Kathrin Niedermayer Darius P. Zlotos Lisa Wiesmüller |
| author_sort | Matthews M. Malka |
| collection | DOAJ |
| description | The 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 <b>M1–M3</b>. The drug conjugates <b>M1–M3</b> combine <b>Olaparib</b>, the first PARP inhibitor approved for clinical use, with <b>Cpd 1</b>, an inhibitor of RAD51 that blocks its HR functions and yet permits RAD51 nucleoprotein filament formation on single-stranded DNA. While in <b>M2</b> and <b>M3</b>, the parental drugs are linked by -CO-(CH<sub>2</sub>)<sub>n</sub>-CO-spacers (n = 2 and 4, respectively), they are directly merged omitting the piperazine ring of <b>Olaparib</b> in <b>M1</b>. Monitoring anti-survival effects of <b>M1</b>–<b>M3</b> 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 <b>M1</b> and <b>M2</b> regardless of their HR capacities, non-TNBC cells were responsive to the merged drug conjugate <b>M1</b> 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. |
| first_indexed | 2024-03-10T09:45:33Z |
| format | Article |
| id | doaj.art-f6654e3bc0d74ca0aa90b5c329c8cb28 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T09:45:33Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-f6654e3bc0d74ca0aa90b5c329c8cb282023-11-22T03:18:14ZengMDPI AGBiomolecules2218-273X2021-07-0111798110.3390/biom11070981Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer CellsMatthews M. Malka0Julia Eberle1Kathrin Niedermayer2Darius P. Zlotos3Lisa Wiesmüller4Department of Pharmaceutical Chemistry, The German University in Cairo, New Cairo City, Main Entrance of Al Tagamoa Al Khames, Cairo 11835, EgyptDepartment of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, 89075 Ulm, GermanyDepartment of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, 89075 Ulm, GermanyDepartment of Pharmaceutical Chemistry, The German University in Cairo, New Cairo City, Main Entrance of Al Tagamoa Al Khames, Cairo 11835, EgyptDepartment of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, 89075 Ulm, GermanyThe 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 <b>M1–M3</b>. The drug conjugates <b>M1–M3</b> combine <b>Olaparib</b>, the first PARP inhibitor approved for clinical use, with <b>Cpd 1</b>, an inhibitor of RAD51 that blocks its HR functions and yet permits RAD51 nucleoprotein filament formation on single-stranded DNA. While in <b>M2</b> and <b>M3</b>, the parental drugs are linked by -CO-(CH<sub>2</sub>)<sub>n</sub>-CO-spacers (n = 2 and 4, respectively), they are directly merged omitting the piperazine ring of <b>Olaparib</b> in <b>M1</b>. Monitoring anti-survival effects of <b>M1</b>–<b>M3</b> 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 <b>M1</b> and <b>M2</b> regardless of their HR capacities, non-TNBC cells were responsive to the merged drug conjugate <b>M1</b> 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.https://www.mdpi.com/2218-273X/11/7/981PARP inhibitorOlaparibRAD51 inhibitordrug conjugatesanticancer drug hybridstriple-negative breast cancer |
| spellingShingle | Matthews M. Malka Julia Eberle Kathrin Niedermayer Darius P. Zlotos Lisa Wiesmüller Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells Biomolecules PARP inhibitor Olaparib RAD51 inhibitor drug conjugates anticancer drug hybrids triple-negative breast cancer |
| title | Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells |
| title_full | Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells |
| title_fullStr | Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells |
| title_full_unstemmed | Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells |
| title_short | Dual PARP and RAD51 Inhibitory Drug Conjugates Show Synergistic and Selective Effects on Breast Cancer Cells |
| title_sort | dual parp and rad51 inhibitory drug conjugates show synergistic and selective effects on breast cancer cells |
| topic | PARP inhibitor Olaparib RAD51 inhibitor drug conjugates anticancer drug hybrids triple-negative breast cancer |
| url | https://www.mdpi.com/2218-273X/11/7/981 |
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