Publication: Evaluación de un nuevo quimiotipo de moduladores de tubulina del dominio de vinca
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2016-04-05
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Universidad Complutense de Madrid
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Abstract
En la actualidad, uno de los mayores problemas de salud pública en los países desarrollados es el cáncer y por este motivo, el estudio de nuevos tratamientos contra dicha enfermedad recibe una especial atención. De todas las terapias existentes, la quimioterapia es la opción preferencial en la mayoría de casos debido a sus buenas expectativas de éxito. La quimioterapia consiste en el bloqueo de una función celular específica mediante el suministro de un agente químico, siendo las dos rutas celulares sobre las que se suele actuar la replicación del material genético y la división celular. Dentro del grupo de tratamientos que actúan sobre la división celular, aquellos que emplean fármacos que alteran el funcionamiento del citoesqueleto se encuentran a la vanguardia de la lucha contra el cáncer. Los microtúbulos, los componentes fundamentales del citoesqueleto, son polímeros dinámicos con aspecto de cilindros huecos compuestos por protofilamentos de tubulina que contactan lateralmente entre sí. Asimismo, dichos protofilamentos son formados mediante la asociación cabeza-cola de heterodímeros de αβ-tubulina. El equilibrio entre el estado dimérico y el estado polimérico es regulado por una dinámica dependiente de la hidrólisis del nucleótido GTP. Los heterodímeros unidos a GTP son más propensos a polimerizar, mientras que los unidos a GDP desplazan el equilibrio hacia la especie libre. Existe una gran colección de agentes químicos que regulan esta dinámica, bien favoreciendo el ensamblaje y/o estabilizando los microtúbulos, o bien favoreciendo el desensamblaje y/o desestabilizando los polímeros. En ambos casos, el correcto funcionamiento de estas estructuras se ve alterado y, con ello, todas las funciones de las que son responsables, tales como la segregación cromosómica o la división de las envueltas nucleares y celulares durante el proceso de replicación...
Nowadays, one of the major public health issues in developed countries is cancer and, for this reason, the study of new treatments against this disease receives today special attention. Among all existing therapies, chemotherapy is preferential choice in most cases because of their high success expectations. Chemotherapy involves the block of a specific cellular function by administering a chemical agent. The two cellular pathways, on which chemotherapy usually acts, are the genetic material replication and the cell division. Within the group of treatments that act on cell division, those using chemotherapy drugs that interact with the cytoskeleton, are at the forefront of the fight against cancer. Microtubules, the major components of cytoskeleton, are dynamic polymers, which look like hollow cylinders. They are made up of tubulin protofilaments, which establish lateral contacts with other protofilaments. Besides, such protofilaments are formed by the head-tail association of αβ-tubulin heterodimers. Balance between dimeric and polymeric state is regulated by a dynamics, which is GTP-hydrolysis dependent. GTP-heterodimers are more likely to polymerize, while GDP-heterodimers drive balance toward free species. There is a large collection of chemical compounds that are able to regulate this dynamics, either promoting tubulin assembly and/or stabilizing microtubules, or promoting disassembly and/or destabilizing polymers. In both cases, proper function of these structures is altered and thus, the whole functions they are responsible for, such as chromosome segregation or division of nuclear and cell envelopes during the replication process, are also altered...
Nowadays, one of the major public health issues in developed countries is cancer and, for this reason, the study of new treatments against this disease receives today special attention. Among all existing therapies, chemotherapy is preferential choice in most cases because of their high success expectations. Chemotherapy involves the block of a specific cellular function by administering a chemical agent. The two cellular pathways, on which chemotherapy usually acts, are the genetic material replication and the cell division. Within the group of treatments that act on cell division, those using chemotherapy drugs that interact with the cytoskeleton, are at the forefront of the fight against cancer. Microtubules, the major components of cytoskeleton, are dynamic polymers, which look like hollow cylinders. They are made up of tubulin protofilaments, which establish lateral contacts with other protofilaments. Besides, such protofilaments are formed by the head-tail association of αβ-tubulin heterodimers. Balance between dimeric and polymeric state is regulated by a dynamics, which is GTP-hydrolysis dependent. GTP-heterodimers are more likely to polymerize, while GDP-heterodimers drive balance toward free species. There is a large collection of chemical compounds that are able to regulate this dynamics, either promoting tubulin assembly and/or stabilizing microtubules, or promoting disassembly and/or destabilizing polymers. In both cases, proper function of these structures is altered and thus, the whole functions they are responsible for, such as chromosome segregation or division of nuclear and cell envelopes during the replication process, are also altered...
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Tesis inédita de la Universidad Complutense de Madrid, Facultad de Ciencias Químicas, leída el 23-10-2015