Publicação
Characterization of the anticancer efficacy and safety profiles of novel synthetic compounds
| Resumo: | Cancer is the most devastating and prevalent disease worldwide. Due to the escalating incidence of cancer, research in this area has been expanding the range of new therapeutic approaches to treat this pathology. Still, there is an urgent need to discover novel and effective drugs for cancer treatment, with improved toxicity profiles and able to overcome the acquisition of resistance to current treatments. The chromene nucleus is a promising biological agent and many chromene-based compounds have already been described bearing anticancer potential. The substitution pattern highly influences the activity and their mode of action, and the synthesis of new derivatives is an important element in the search for improved drug candidates. Hence, the major aim of this work is to exploit the anticancer potential of new compounds based on the chromene scaffold and to study their mode of action, using two cancer models: breast cancer (BC) and renal cell carcinoma (RCC). An in vitro characterization of the anticancer activity for the synthesized compounds was performed in both BC and RCC models using a panel of different cancer cell lines. The toxicity of the most active compounds was assessed in non-neoplastic cells and in vivo Caenorhabditis elegans and mouse models. Efficacy studies were performed using the chorioallantoic membrane (CAM) of the chicken embryo and mouse xenograft. For both BC and RCC, the tested compounds revealed IC50 in the nanomolar range with superior selectivity indexes than those obtained for reference drugs. For BC model, the novel compounds were capable to inhibit cell proliferation, induce cell death via apoptosis intrinsic pathway and trigger cell cycle arrest. In vivo, the chromenes were responsible for tumor regression in the CAM model and tumor growth inhibition in mice xenografts. The novel chromenes showed considerably higher IC50 for non-neoplastic cells and no toxicity in C. elegans or mouse models, with preservation of organ structural architecture and biochemical parameters. The chromenes used on the RCC model had a similar mode of action than in BC leading to inhibition of cell proliferation, migration, and invasion, triggering cell death by apoptosis, cell cycle arrest and inhibition of glucose metabolism. In the CAM model, chromenesinduced tumor regression and inhibited angiogenesis. The new chromenes maintained low IC50 in drug resistant cancer cells, with good selectivity indexes, and preserving their anticancer potency. This work provides a valuable contribution to the use of chromene derivatives as anticancer agents for the treatment of BC and RCC even after acquisition of targeted drug resistance. Importantly, the novel compounds revealed a new mode of action, which can be valuable for the treatment of aggressive cancers. Thus, the work performed in this thesis reinforces the importance of the design of novel molecules for cancer treatment, leading to the improvement of current therapeutic options. |
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| Autores principais: | Pontes, Olívia Alexandra Elias |
| Assunto: | Breast cancer Renal cell carcinoma Chromenes Resistance to treatment Cancro da mama Carcinoma de células renais Cromenos Resistência |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade do Minho |
| Idioma: | inglês |
| Origem: | RepositóriUM - Universidade do Minho |
| Resumo: | Cancer is the most devastating and prevalent disease worldwide. Due to the escalating incidence of cancer, research in this area has been expanding the range of new therapeutic approaches to treat this pathology. Still, there is an urgent need to discover novel and effective drugs for cancer treatment, with improved toxicity profiles and able to overcome the acquisition of resistance to current treatments. The chromene nucleus is a promising biological agent and many chromene-based compounds have already been described bearing anticancer potential. The substitution pattern highly influences the activity and their mode of action, and the synthesis of new derivatives is an important element in the search for improved drug candidates. Hence, the major aim of this work is to exploit the anticancer potential of new compounds based on the chromene scaffold and to study their mode of action, using two cancer models: breast cancer (BC) and renal cell carcinoma (RCC). An in vitro characterization of the anticancer activity for the synthesized compounds was performed in both BC and RCC models using a panel of different cancer cell lines. The toxicity of the most active compounds was assessed in non-neoplastic cells and in vivo Caenorhabditis elegans and mouse models. Efficacy studies were performed using the chorioallantoic membrane (CAM) of the chicken embryo and mouse xenograft. For both BC and RCC, the tested compounds revealed IC50 in the nanomolar range with superior selectivity indexes than those obtained for reference drugs. For BC model, the novel compounds were capable to inhibit cell proliferation, induce cell death via apoptosis intrinsic pathway and trigger cell cycle arrest. In vivo, the chromenes were responsible for tumor regression in the CAM model and tumor growth inhibition in mice xenografts. The novel chromenes showed considerably higher IC50 for non-neoplastic cells and no toxicity in C. elegans or mouse models, with preservation of organ structural architecture and biochemical parameters. The chromenes used on the RCC model had a similar mode of action than in BC leading to inhibition of cell proliferation, migration, and invasion, triggering cell death by apoptosis, cell cycle arrest and inhibition of glucose metabolism. In the CAM model, chromenesinduced tumor regression and inhibited angiogenesis. The new chromenes maintained low IC50 in drug resistant cancer cells, with good selectivity indexes, and preserving their anticancer potency. This work provides a valuable contribution to the use of chromene derivatives as anticancer agents for the treatment of BC and RCC even after acquisition of targeted drug resistance. Importantly, the novel compounds revealed a new mode of action, which can be valuable for the treatment of aggressive cancers. Thus, the work performed in this thesis reinforces the importance of the design of novel molecules for cancer treatment, leading to the improvement of current therapeutic options. |
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