Publicação
Unraveling the molecular targets of new ruthenium-based anticancer drugs
| Resumo: | Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. Nowadays, there are limited chemotherapeutic agents available for the treatment of CRC, which is frequently accompanied by severe side effects and acquisition of resistance. Moreover, CRC that harbor mutations in KRAS or BRAF and/or PIK3CA associated with EGFR overexpression do not respond to EGFR inhibitors available. This constitutes a clinical relevant problem that needs to be overcome. Ruthenium (Ru) drugs had arisen as one of the most promising metallodrugs with characteristics that increase their specificity and selectivity toward cancer cells. For these reasons, three new multifunctional polymer-metal conjugates of ruthenium (RuPMC) were synthesized, one taking advantage of Ru anticancer properties (PMC79) and two resulting from Ru functionalization to improve the targeting approach (PMC78 and PMC85). Here, we aimed to assess the effect of the newly synthesized Ru compounds in CRC cells with different genetic background and unravel their mechanisms of action and molecular targets. For that matter, we studied the effect of Ru compounds on cell proliferation, cell cycle and cell death. Further, we evaluated the effect of Ru compounds on the expression of proteins associated to different signaling pathways and of GLUT1. We also analyzed their effect on actin filaments of the cytoskeleton. The results showed that our compounds induce apoptosis but do not interfere with cell cycle. Moreover, the Ru compounds influence differently the expression of AKT and ERK. The most interesting result was observed with PMC79 in SW480 cells, which decreased the expression levels of p-AKT and p-ERK proteins. We also observed that the RuPMCs affect the actin cytoskeleton and β-actin expression. Additionally, we could observe that PMC79 upregulated the expression of GLUT1 in SW480 cells, and the combination of PMC79 with STF- 31 results in a synergistic effect which potentiate the Ru compound effect. Our compounds seem to affect differently the two cell lines, being SW480 the most sensitive cell line, mainly to the compound PMC79, however, PMC78 and PMC85 also showed very promising results. In this work, the first steps were taken toward the discovery of the molecular targets and mechanism of action of new Ru compounds in CRC cells, that might be promising agents for CRC therapy. |
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| Autores principais: | Brás, Ana Rita Pinto |
| Assunto: | Colorectal cancer Ruthenium Apoptosis KRAS mutations Actin cytoskeleton GLUT1 Cancro colorretal Ruténio Apoptose Mutações em KRAS Citoesqueleto de actina |
| Ano: | 2018 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. Nowadays, there are limited chemotherapeutic agents available for the treatment of CRC, which is frequently accompanied by severe side effects and acquisition of resistance. Moreover, CRC that harbor mutations in KRAS or BRAF and/or PIK3CA associated with EGFR overexpression do not respond to EGFR inhibitors available. This constitutes a clinical relevant problem that needs to be overcome. Ruthenium (Ru) drugs had arisen as one of the most promising metallodrugs with characteristics that increase their specificity and selectivity toward cancer cells. For these reasons, three new multifunctional polymer-metal conjugates of ruthenium (RuPMC) were synthesized, one taking advantage of Ru anticancer properties (PMC79) and two resulting from Ru functionalization to improve the targeting approach (PMC78 and PMC85). Here, we aimed to assess the effect of the newly synthesized Ru compounds in CRC cells with different genetic background and unravel their mechanisms of action and molecular targets. For that matter, we studied the effect of Ru compounds on cell proliferation, cell cycle and cell death. Further, we evaluated the effect of Ru compounds on the expression of proteins associated to different signaling pathways and of GLUT1. We also analyzed their effect on actin filaments of the cytoskeleton. The results showed that our compounds induce apoptosis but do not interfere with cell cycle. Moreover, the Ru compounds influence differently the expression of AKT and ERK. The most interesting result was observed with PMC79 in SW480 cells, which decreased the expression levels of p-AKT and p-ERK proteins. We also observed that the RuPMCs affect the actin cytoskeleton and β-actin expression. Additionally, we could observe that PMC79 upregulated the expression of GLUT1 in SW480 cells, and the combination of PMC79 with STF- 31 results in a synergistic effect which potentiate the Ru compound effect. Our compounds seem to affect differently the two cell lines, being SW480 the most sensitive cell line, mainly to the compound PMC79, however, PMC78 and PMC85 also showed very promising results. In this work, the first steps were taken toward the discovery of the molecular targets and mechanism of action of new Ru compounds in CRC cells, that might be promising agents for CRC therapy. |
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