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From 2D to 3D: Copper compounds as a new therapeutic approach in colorectal cancer
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O cancro é a segunda causa de morte no mundo e os tratamentos atuais como a quimioterapia são limitados pela sua toxicidade, baixa especificidade e desenvolvimento de resistência. De modo a combater estes problemas, este trabalho avaliou o potencial quimioterapêutico de compostos de cobre e manganês em linhas de cancro colorretal (HCT116 e HCT116-DoxR, uma variante com resistência à doxorrubicina) e numa linha não-tumoral de fibroblastos. Os ensaios de citotoxicidade demonstraram que todos os compostos estudados têm valores de IC50 mais pequenos do que a doxorrubicina, com os compostos Cu-4Py-terpy-Poly1D e Cu-Methoxy em particular a demonstrar altos índices de seletividade. A sua atividade foi ainda avaliada em esferoides 3D, sendo que os valores de IC50 obtidos foram maiores do que os observados em culturas 2D, o que reflete a complexidade das primeiras estruturas.
Estudos mecanísticos demonstraram que ambos os compostos induziram apoptose intrínseca, tal como evidenciado pela despolarização da membrana mitocondrial e maior produção de ROS por eles induzida. Os compostos induzem também autofagia, sugerindo uma atividade anticancerígena multimodal. A combinação destes compostos com o FOLFOX (FF) resultou em níveis de apoptose ainda maiores, sugerindo uma potencial ação sinergística destes componentes. Adicionalmente, os dois compostos demonstraram também ter potencial citostático, ao atrasar o ciclo celular na fase S. Estudos in vivo demonstraram uma atividade anti-angiogénica destes compostos sem nenhuma toxicidade detetada.
Em suma, os compostos Cu-4Py-terpy-Poly1D e Cu-Methoxy tornam-se candidatos promissores como agentes anticancerígenos, particularmente em tumores resistentes a outros fármacos. Futuros ensaios devem incluir estudos mecanísticos mais aprofundados, possíveis modificações estruturais e testes em modelos mais aproximados a humanos de modo a se poder avançar para potenciais aplicações clínicas.
Cancer is the second leading cause of death worldwide, and current treatments such as chemotherapy remain limited by toxicity, low specificity, and the development of resistance. To address these challenges, this study evaluated the chemotherapeutic potential of novel copper and manganese complexes in colon cancer cell lines (HCT116 and the doxorubicin-resistant variant, HCT116-DoxR), as well as in non-tumour fibroblasts. Cytotoxicity assays demonstrated that all complexes exhibited lower IC50 values than doxorubicin, with copper-based complexes Cu-4Py-terpy-Poly1D and Cu-Methoxy showing particularly high selectivity indices. Their activity was further validated in 3D spheroids, where higher IC50 values were observed compared to 2D cultures, reflecting the complexity of tumour-like structures. Mechanistic studies revealed that both complexes induce intrinsic apoptosis, as evidenced by mitochondrial membrane depolarization and increased ROS production, and they also triggered autophagy, suggesting multimodal anticancer activity. In combination with the FOLFOX (FF) regimen, apoptosis was significantly enhanced, with synergistic effects observed. Furthermore, both copper complexes displayed a cytostatic potential by arresting cells in the S phase, while in vivo assays in chicken embryos demonstrated promising antiangiogenic activity without detectable toxicity. Overall, Cu-4Py-terpy-Poly1D and Cu-Methoxy emerge as promising candidates for further development as anticancer agents, particularly against drug-resistant tumours. Future work should include in-depth mechanistic studies, structural modifications, and in vivo testing to advance their potential clinical application.
Cancer is the second leading cause of death worldwide, and current treatments such as chemotherapy remain limited by toxicity, low specificity, and the development of resistance. To address these challenges, this study evaluated the chemotherapeutic potential of novel copper and manganese complexes in colon cancer cell lines (HCT116 and the doxorubicin-resistant variant, HCT116-DoxR), as well as in non-tumour fibroblasts. Cytotoxicity assays demonstrated that all complexes exhibited lower IC50 values than doxorubicin, with copper-based complexes Cu-4Py-terpy-Poly1D and Cu-Methoxy showing particularly high selectivity indices. Their activity was further validated in 3D spheroids, where higher IC50 values were observed compared to 2D cultures, reflecting the complexity of tumour-like structures. Mechanistic studies revealed that both complexes induce intrinsic apoptosis, as evidenced by mitochondrial membrane depolarization and increased ROS production, and they also triggered autophagy, suggesting multimodal anticancer activity. In combination with the FOLFOX (FF) regimen, apoptosis was significantly enhanced, with synergistic effects observed. Furthermore, both copper complexes displayed a cytostatic potential by arresting cells in the S phase, while in vivo assays in chicken embryos demonstrated promising antiangiogenic activity without detectable toxicity. Overall, Cu-4Py-terpy-Poly1D and Cu-Methoxy emerge as promising candidates for further development as anticancer agents, particularly against drug-resistant tumours. Future work should include in-depth mechanistic studies, structural modifications, and in vivo testing to advance their potential clinical application.
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Cancer Cell death Chemotherapy Copper Cytotoxicity HCT116-DoxR cells