Efecto de la nicotinamida como inhibidor de la poli (ADP-ribosa) polimerasa en cáncer de mama deficiente de BRCA1
Introduction: The nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is essential for the repair of single-strand breaks in DNA by means of base excision repair and represents an important target in the therapy cancer. Inhibitors of PARP-1 have been shown to potentiate the cytotoxic effects of i...
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| Format: | doctoral thesis |
| Status: | Published version |
| Publication Date: | 2014 |
| Country: | México |
| Institution: | Universidad Autónoma Metropolitana |
| Repository: | Repositorio Institucional de la UAM Iztapalapa |
| Language: | Spanish |
| OAI Identifier: | oai:bindani.izt.uam.mx:wp988j98c |
| Online Access: | https://doi.org/10.24275/uami.wp988j98c |
| Access Level: | Open access |
| Keyword: | info:eu-repo/classification/LEM/Enzimas info:eu-repo/classification/LEM/Breast -- Cancer info:eu-repo/classification/LEM/Enzymes info:eu-repo/classification/LEM/NAD-ADP-ribosyltransferase info:eu-repo/classification/LEM/Biología experimental info:eu-repo/classification/LEM/Biology, Experimental info:eu-repo/classification/LEM/Poli ADP ribosa polimerasa info:eu-repo/classification/LEM/Mamas -- Cáncer info:eu-repo/classification/cti/3 |
| Summary: | Introduction: The nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is essential for the repair of single-strand breaks in DNA by means of base excision repair and represents an important target in the therapy cancer. Inhibitors of PARP-1 have been shown to potentiate the cytotoxic effects of ionizing radiation and chemotherapeutic agents such as carboplatin that DNA damaging or inhibitors topoisomerase I. Nicotinamide has been described as an inhibitor of PARP-1 in vitro, and the vast majority of PARP inhibitors are based on their chemical structure. Results in vitro and in vivo and clinical trials recently, suggest that PARP inhibitors can be used as sensitizers to chemotherapy or radiotherapy as well as monotherapy, killing specifically cancer cells with defective in repair mechanisms DNA, particularly those cancers with mutations in the genes encoding proteins BRCA1 and BRCA2. In this experimental strategy has been called "synthetic lethality". In this study we analyzed the effect of nicotinamide in cancer cells proficient and deficient BRCA1. Methods: The effect of the nicotinamide as an inhibitor of PARP-1 was determined by activity assays in vitro PARP-1 and MDA-MB-436 cells. This effect was verified by immunofluorescence in mammary carcinoma cells treated with nicotinamide in the presence of DNA damage. Subsequently, we analyzed the effect of nicotinamide in combination with cisplatin in cell viability assays in MDA-MB-436 (BRCA1-deficient), MDA MB-231 (BRCA1-proficient) and MCF-7 (BRCA1, low levels of expression) cancer cells. Finally, we analyze the effect of nicotinamide as radiosensitizer by clonogenic assays. Results: our results demonstrated that nicotinamide inhibits PARP-1 activity in vitro and in MDA-MB-436 mammary carcinoma BRCA1-deficient. This effect was also observed in breast cancer cells in the presence of DNA damage. Later demonstrated that nicotinamide decreases viability of MDA-MB-436, MDA-MB-231 and MCF-7. Analysis of the data by the isobologram method showed that the combination of nicotinamide and cisplatin produced a synergistic antiproliferative effect in MDA-MB-436 and MCF-7 cancer cells. Finally we observed that the nicotinamide also sensitizes MDA-MB436 and MDA-MB-231 cancer cells to ionizing radiation. Discussion: these results suggesting that nicotinamide sensitizes cancer cells cisplatin treatment and that this effect is influenced by the status of BRCA1, however in MDA-MB-231 cells should take into account other genetic factors as the status triple negative of cell line. On the other hand, the response to treatment with nicotinamide y ionizing radiation in MCF-7 cells could be associated to deficiency of caspase 3, because it has been reported an increase resistance to ionizing radiation in cancer cells deficient in caspase 3. Conclusion: we results suggest that nicotinamide may be used with sensitizer to chemotherapy and radiotherapy in breast cancer more selectively in BRCA1 deficient BRCA1 cancer cells. Interestingly, these results also suggest that inhibition of PARP-1 by nicotinamide may be favoring synthetic lethality in breast cancer cells. |
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