PHOTO-CONTROLLED AUTOPHAGY INHIBITORS FOR SELECTIVE ELIMINATION OF CANCER STEM CELLS
The lack of effective therapies for resistant cancers is a critical challenge in pharmacology today. Due to specific characteristics of cancer stem cells (CSCs), such as self-renewal and a low proliferation ratio, conventional chemotherapy has shown limited effectiveness against them. Therefore, sig...
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| Tipo de recurso: | otro |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/420858 |
| Acceso en línea: | http://hdl.handle.net/10261/420858 |
| Access Level: | acceso abierto |
| Palabra clave: | Cancer stem cells http://metadata.un.org/sdg/3 http://metadata.un.org/sdg/9 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation |
| Sumario: | The lack of effective therapies for resistant cancers is a critical challenge in pharmacology today. Due to specific characteristics of cancer stem cells (CSCs), such as self-renewal and a low proliferation ratio, conventional chemotherapy has shown limited effectiveness against them. Therefore, significant efforts are being made to find specific treatment strategies targeting CSCs and blocking their various survival mechanisms. However, finding selective and safe drugs for these cells is challenging. For this purpose, photopharmacology is a helpful tool that allows us to precisely direct drug action, minimizing side effects and maximizing effectiveness. It is based on using small molecules whose biological activity is controlled by external light. In this research, photo-activable compounds based on hydroxychloroquine (HCQ), an autophagy inhibitor believed to eliminate CSCs, have been characterised; in particular, we studied their stability, photochemical properties, and biological activity. Firstly, after a detailed photochemical characterization, we chose MCS2065 for further studies due to its promising photochemical profile and low activity in the dark. Secondly, its activity was explored in the human breast cancer cell line MCF7 grown in adherence under various light conditions and illumination periods. In these models, MCS2065 showed activity after short illumination, but not in the dark. Additionally, to facilitate further studies, we performed two complementary assays: combination studies to analyze the synergistic effects of HCQ with other antiproliferative agents, and internalization assays for future localization studies. Thirdly, several pharmacological assays were performed on MCF7 spheres to test the activity of HCQ and MCS2065 in dark and light. To validate spheres as the most suitable model for studying CSCs, we cultured them over multiple generations. This allowed us to correlate the effects of autophagy inhibitors on cell viability with the gene expression of CSC markers, analyzed by quantitative PCR (qPCR). The results were then compared with those obtained from adherence cultures. |
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