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Assement of biological action of new drug candidate with potential immune check-point activity for cancer treatment
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O cancro continua a ser uma das principais causas de mortalidade no mundo, e um dos fatores-chave que leva à progressão desta doença é a expressão de glicanos aberrantes na superfície das células tumorais. As imunoterapias, como os inibidores de pontos de controlo imunitário, transformaram as terapias contra o cancro, particularmente os anticorpos monoclonais direcionados ao eixo PD-1/PD-L1. No entanto, a sua aplicação está comprometida por diversas limitações, incluído os custos elevados de produção, potenciais efeitos adversos a longo prazo, bem como risco acrescidos de autoimunidade. As lectinas, devido à sua capacidade de reconhecer glicanos sobre expressos na superfície das células tumorais, e as pequenas moléculas surgiram como alternativas promissoras. Neste trabalho, avaliámos os efeitos antitumorais e biológicos de três lectinas de algas vermelhas, Solieria filiformis (SFL), Meristiella echinocarpa (MEL) e Amansia multifida (AML), bem como da pequena molécula Sonidegib. Entre as lectinas, a SFL apresentou o efeito citotóxico mais pronunciado, induzindo apoptose sem necrose significativa para a linha celular de carcinoma do pulmão. Também demonstrou uma capacidade moderada de ligação com a proteína PD L1, sugerindo um potencial papel na disrupção do eixo PD-1/PD-L1. Paralelamente, o tratamento com Sonidegib induziu alterações dependentes da dose, comprometendo significativa mente a morfologia e a viabilidade celular na linhagem celular monocítica. Em contraste, as lectinas MEL e AML exibiram uma atividade citotóxica menos pronunciada, possivelmente devido à sua menor afinidade pelos glicanos expressos na superfície das células tumorais. De um modo geral, compreender o potencial das lectinas e de pequenas moléculas na modulação da resposta imunitária e da progressão tumoral poderá contribuir para o desenvolvimento e implementação de novas abordagens terapêuticas mais eficazes no trata mento do cancro.
Cancer remains one of the leading causes of mortality in the world, and one of the key factors that leads to the disease progression is the expression of aberrant glycans at the tumour cells surface. Immunotherapies such as immune checkpoint inhibitors have transformed cancer therapies, particularly monoclonal antibodies targeting the PD-1/PD-L1 axis. However, their use as therapeutics is limited by its associated elevated production costs, potential long-term adverse effects, as well as increased risk for autoimmune disease. Lectins, due to their ability to recognise overexpressed glycans on the surface of tumour cells, and small molecules have emerged as promising alternatives. In this work, we evaluated the antitumor and biological effects of three red algae lectins, Solieria filiformis (SFL), Meristiella echinocarpa (MEL) and Amansia multifida (AML), as well as the small molecule Sonidegib. Among the lectins, SFL exhibited the most pronounced cytotoxic effect, inducing apoptosis without significant necrosis for the lung carcinoma cell line. Additionally, demonstrated a moderate binding to the protein PD-L1, suggesting a potential role in disrupt PD-1/PD-L1 axis. In parallel, Sonidegib treatment induced dose-dependent alterations which compromised cell morphology and viability at monocytic lineage. In contrast, MEL and AML displayed weaker cytotoxic activity, most likely due to limited affinity for the glycans expressed on the tumour cells surface. Overall, understanding the potential of lectins and small molecules as modulators of the immune response and tumour progression may contribute to the development of novel therapy strategies for more effective cancer treatments.
Cancer remains one of the leading causes of mortality in the world, and one of the key factors that leads to the disease progression is the expression of aberrant glycans at the tumour cells surface. Immunotherapies such as immune checkpoint inhibitors have transformed cancer therapies, particularly monoclonal antibodies targeting the PD-1/PD-L1 axis. However, their use as therapeutics is limited by its associated elevated production costs, potential long-term adverse effects, as well as increased risk for autoimmune disease. Lectins, due to their ability to recognise overexpressed glycans on the surface of tumour cells, and small molecules have emerged as promising alternatives. In this work, we evaluated the antitumor and biological effects of three red algae lectins, Solieria filiformis (SFL), Meristiella echinocarpa (MEL) and Amansia multifida (AML), as well as the small molecule Sonidegib. Among the lectins, SFL exhibited the most pronounced cytotoxic effect, inducing apoptosis without significant necrosis for the lung carcinoma cell line. Additionally, demonstrated a moderate binding to the protein PD-L1, suggesting a potential role in disrupt PD-1/PD-L1 axis. In parallel, Sonidegib treatment induced dose-dependent alterations which compromised cell morphology and viability at monocytic lineage. In contrast, MEL and AML displayed weaker cytotoxic activity, most likely due to limited affinity for the glycans expressed on the tumour cells surface. Overall, understanding the potential of lectins and small molecules as modulators of the immune response and tumour progression may contribute to the development of novel therapy strategies for more effective cancer treatments.
Descrição
Palavras-chave
Cancer therapies Immune checkpoint inhibitors (ICIs) Solieria filiformis (SFL) Meristiella echinocarpa (MEL) Amansia multifida (AML) Apoptosis