Dados do Resumo

Título

Biophysical perturbations of mitochondrial-mimicking membranes by triterpenoids: divergent effects on non-malignant and malignant human cells

Introdução

Therapeutic autophagy-targeting has been highlighted as a good candidate for overcoming tumor resistance to radio, chemo, or photo-based therapies. Some natural compounds that share assembly properties like cholesterol, such as the triterpenoids Ursolic acid (UA) and its isomer, betulinic acid (BA), may modulate autophagy as a cell death mechanism in tumor cells. UA and BA's cholesterol-like properties could enhance their therapeutic potential against cancer. However, more research is needed to understand these interactions and their implications fully. Also, it remains unclear whether UA behaves similarly to BA in non-malignant human cells, particularly in their ability to interact with and potentially damage membranes.

Objetivo

This study aimed to contribute to understanding how natural compounds like UA and BA can be used in cancer therapy, potentially leading to the development of more effective treatment strategies. Furthermore, considering their cholesterol-like assembly properties, we will delve into their biophysical effects on cellular membranes, which could provide additional insights into their mechanism of action and therapeutic potential.

Métodos

Using non-malignant keratinocytes (HaCaT) and various human malignant cells (A549, PC3, SKMEL-25, and SKMEL-28), we employed several assays, including immunocytochemical, cytometric, and biochemical experiments, along with membrane disruption evaluation using mimicked protein-free membranes (liposomes, giant unilamellar vesicles, GUVs) and human erythrocytes.

Resultados

Our findings reveal a fascinating dichotomy. UA may disrupt lysosomal integrity and function in cancer cells, leading to autophagy impairment or cell death. This phenotype, characterized by increased lysosomal enzyme expression and activity, changes in membrane composition, and extracellular secretion, makes cancer cells more susceptible to UA-induced lysosomal destabilization, potentially activating cell death pathways. In contrast, in non-malignant cells, unlike BA, UA's ability to maintain cellular balance and minimize long-term damage makes it a promising candidate for therapeutic applications.

Conclusões

Considering the findings and cellular effects of triterpenoids, we propose a link between the biophysical perturbation of mitochondrial-mimicking membranes and triterpenoids' ability to induce lysosomal-mitochondrial stress and impaired autophagy. Our study, however, has its limitations. Conducted in vitro, the results may not directly apply to in vivo conditions. Despite these limitations, this research offers a crucial basis for further exploration into the therapeutic capabilities of cholesterol-like compounds, specifically concerning cancer therapy.

Financiador do resumo

This work was supported by PNPD (Programa Nacional de Pós Doutorado)/CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior)/FINEP (Financiadora de Estudos e Projetos) grant number 02533/09-0, Brazil; and by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) grants 2012/50680-5, 2013/07937-8 and 2016/07642-6.

Palavras Chave

Betulinic acid; Ursolic acid; Autophagy