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Avaliação de complexos metálicos de Cobre (Cu(II)) e de Platina (Pt(II)) como agentes antiproliferativos em células tumorais
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Resumo(s)
O cancro é uma doença complexa e devastadora que afeta milhões de pessoas em todo o mundo, caracterizada pelo crescimento descontrolado de células anormais no organismo. A quimioterapia é um dos tratamentos mais comuns para o cancro, consistindo na administração de agentes químicos que visam destruir as células cancerígenas ou inibir o seu crescimento.
Dentro dos agentes químicos, os complexos metálicos têm despertado o interesse na investigação médica, pois mostram elevado potencial como agentes quimioterapêuticos eficazes, devido às suas propriedades únicas que permitem a combinação com diversos ligandos existindo uma maior seletividade no ataque às células malignas, minimizando o impacto nas células saudáveis. Este avanço representa uma promissora perspetiva para o tratamento do cancro, em busca de alternativas mais eficazes, menos tóxicas e que evitem o aparecimento de resistências.
Neste trabalho, vários complexos de cobre (Cu(II)) e de platina (Pt(II)) foram testados em termos de atividade antiproliferativa em culturas 2D de carcinoma colorretal, carcinoma colorretal resistente à doxorrubicina, carcinoma do ovário e em fibroblastos primários humanos.
Entre os complexos testados, os complexos Cu1a, Cu1b e Pt1a mostram-se como os mais promissores com maiores índices de seletividade para as células de carcinoma de colorretal resistente à doxorrubicina (HCT116doxR; IC50 de 0,239, 0,290 e 0,683 respetivamente). Os resultados revelam que estes complexos são capazes de internalizar nas células HCT116doxR ao fim de 3h levando à formação de ROS com consequente alteração do potencial de membrana mitocondrial e indução de morte celular programada pela via apoptótica intrínseca e por autofagia. Estes complexos interferem ainda na progressão do ciclo celular com formação de células senescentes, conseguem clivar o DNA plasmídico através de mecanismos oxidativos e interagir com a albumina sérica bovina (BSA). Verificou-se ainda que os três complexos atrasam o processo de migração celular, mas apenas o complexo Pt1a parece ter algum efeito na retardação da neovascularização.
Cancer is a complex and devastating disease that affects millions of individuals worldwide. It is characterized by the uncontrolled growth of abnormal cells within the body. Chemotherapy is one of the most common treatments for cancer, involving the administration of chemical agents aimed at destroying cancer cells or inhibiting their growth. Among these chemical agents, metal complexes have attracted considerable garnered interest in medical research due to their high potential as effective chemotherapeutic agents. This can be credited to their unique properties that enable them to combine with various ligands, allowing for greater selectivity in targeting malignant cells while minimizing the impact on healthy cells. This advancement represents a promising perspective for cancer treatment, seeking more effective and less toxic alternatives while mitigating the development of resistance. In this study, several copper (Cu(II)) and platinum (Pt(II)) complexes were assessed for their anti-proliferative activity in 2D cultures of colorectal carcinoma, doxorubicin-resistant colorectal carcinoma, ovarian carcinoma, and primary human fibroblasts. Among the tested complexes, Cu1a, Cu1b, and Pt1a complexes emerged as the most promising ones, displaying higher selectivity indices for doxorubicin-resistant colorectal carcinoma cells (HCT116doxR) with IC50 values of 0.239, 0.290, and 0.683, respectively. The results demonstrate that these complexes are capable of internalizing HCT116doxR cells within 3 hours, leading to the generation of reactive oxygen species (ROS), subsequent alteration of mitochondrial membrane potential, and induction of programmed cell death through the intrinsic apoptotic pathway and autophagy. Furthermore, these complexes interfere with cell cycle progression, induce cellular senescence, cleave plasmid DNA via oxidative mechanisms, and interact with bovine serum albumin (BSA). It was also observed that all three complexes delay the cell migration process, although only Pt1a appears to have some effect on retarding neovascularization.
Cancer is a complex and devastating disease that affects millions of individuals worldwide. It is characterized by the uncontrolled growth of abnormal cells within the body. Chemotherapy is one of the most common treatments for cancer, involving the administration of chemical agents aimed at destroying cancer cells or inhibiting their growth. Among these chemical agents, metal complexes have attracted considerable garnered interest in medical research due to their high potential as effective chemotherapeutic agents. This can be credited to their unique properties that enable them to combine with various ligands, allowing for greater selectivity in targeting malignant cells while minimizing the impact on healthy cells. This advancement represents a promising perspective for cancer treatment, seeking more effective and less toxic alternatives while mitigating the development of resistance. In this study, several copper (Cu(II)) and platinum (Pt(II)) complexes were assessed for their anti-proliferative activity in 2D cultures of colorectal carcinoma, doxorubicin-resistant colorectal carcinoma, ovarian carcinoma, and primary human fibroblasts. Among the tested complexes, Cu1a, Cu1b, and Pt1a complexes emerged as the most promising ones, displaying higher selectivity indices for doxorubicin-resistant colorectal carcinoma cells (HCT116doxR) with IC50 values of 0.239, 0.290, and 0.683, respectively. The results demonstrate that these complexes are capable of internalizing HCT116doxR cells within 3 hours, leading to the generation of reactive oxygen species (ROS), subsequent alteration of mitochondrial membrane potential, and induction of programmed cell death through the intrinsic apoptotic pathway and autophagy. Furthermore, these complexes interfere with cell cycle progression, induce cellular senescence, cleave plasmid DNA via oxidative mechanisms, and interact with bovine serum albumin (BSA). It was also observed that all three complexes delay the cell migration process, although only Pt1a appears to have some effect on retarding neovascularization.
Descrição
Palavras-chave
Cancro Quimioterapia Complexos metálicos Cobre Platina Citotoxicidade