The effect of chromatin compaction modification on the efficacy of anticancer medicaments
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Título: | The effect of chromatin compaction modification on the efficacy of anticancer medicaments |
Autor/a: | González Carro, Sara |
Dirección/Titoría: | Domínguez Puente, Fernando |
Centro/Departamento: | Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas Universidade de Santiago de Compostela. Centro Internacional de Estudos de Doutoramento e Avanzados (CIEDUS) Universidade de Santiago de Compostela. Escola de Doutoramento Internacional en Ciencias da Saúde Universidade de Santiago de Compostela. Programa de Doutoramento en Nanomedicina |
Palabras chave: | anticancer medicaments | Drug resistance | Tumor microenvironment | |
Data: | 2020 |
Resumo: | DNA binding drugs play a major role in cancer therapy. However, their success rate is far from optimal, therefore it is essential to develop new strategies and approaches to enhance patient survival. Drugs that act by binding to DNA face difficulties to bind to DNA once inside the cell. For example, only 1% of CDDP (cisplatin) binds to nuclear DNA. Genomic DNA of eukaryotic cells is packaged in a nuclear complex associated with proteins and RNA called chromatin. Processes like transcription or replication require access to genomic DNA, in which chromatin serves as a regulatory platform by limiting access to DNA. My goal is to explore whether chromatin has a similar effect on drug-DNA binding. Previous results obtained in our group show that Ag3-AQCs (Atomic Quantum Clusters of 3 atoms of silver) reduce chromatin compaction and improve the efficacy of drugs like oxaliplatin, carboplatin, gemcitabine, CDDP and DOX (doxorubicin). We explored whether this mechanism is specific or if a reduction in chromatin compaction can improve DNA accessibility to drugs and, therefore, chemotherapeutic medicaments efficacy. To test this hypothesis, we quantified CDDP by ICP-MS (induced coupled plasma mass spectrometry) and DOX (by flow cytometry and confocal microscopy) binding to DNA in various models of cells with reduced chromatin compaction. First, we compared two murine ESCs (embryonic stem cell) from CJ7 parental line. These two lines only differentiate in an insertion in zmym2 gene, resulting in reduced chromatin compaction. I also analyzed the effect of a partial depletion of histone H4 in a yeast model. Then, I wanted to test a model with potential clinical application. CASP8AP2 (Caspase 8 associated protein 2), a transcriptional regulator of histone genes and CAF-1 (Chromatin-Assembly Factor 1), a histone chaperone that specifically deposits newly synthesized H3-H4 histones onto replicating DNA,were silenced in A549 lung adenocarcinoma cell line using siRNAs. Lastly, I studied the effect of iHDACs (histone deacetylase inhibitors), extensively studied and in clinical use in cancer treatment. I selected three iHDACs: trichostatin A (TSA), suberanilohydroxamic (SAHA) and valproate (VPA) with different HDACs targets. Both ESC and yeast models, confirm the increased levels of CDDP and DOX binding to DNA in cells with reduced chromatin compaction compared with wild types with rise of almost 400 % and 300% of CDDP and DOX, respectively, binding to DNA in yeast model. CAF-1 silencing results in an increase of 50 % of DOX binding, while CASP8AP2 silencing only modifies DOX binding by 10 %.iHDACs TSA and SAHA increase CDDP and DOX binding to DNA, while VPA does not. Increasing of the binding of the drugs also increase their effect on cell viability. Thus, potentiation of the efficacy of anticancer medicaments, suchs as CDDP and DOX, by iHDACs TSA and SAHA could be at least partially explained by the reduction in chromatin compaction, that results in increased binding of anticancer drugs to DNA. |
URI: | http://hdl.handle.net/10347/23183 |
Dereitos: | Attribution-NonCommercial-NoDerivatives 4.0 Internacional |
Coleccións
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- Área de Ciencias da Saúde [1252]
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