Characteristics of toxicity promoted by oxysterols in mesenchymal stem cells derived from bone marrow of patients with acute myeloid leukemia

A leucemia mieloide aguda (LMA) é uma neoplasia que afeta a maturação das células-tronco hematopoiéticas (CTH), comprometendo a produção dos componentes saudáveis da medula óssea. A LMA acomete pessoas de todas as idades e a sobrevida de indivíduos portadores da doença ainda é baixa. Vários estudos relatam a interação das células-tronco mesenquimais (CTM) na regulação e manutenção das CTH, onde podem secretar mediadores no microambiente que estão envolvidos na malignidade dos tumores hematológicos. Desse modo, são imprescindíveis novas formas de adjuvantes terapêuticos no combate ao câncer. Como forma de tratamento adjuvante, estudos demonstraram que substâncias como oxisteróis, que são compostos oxidados do colesterol, tem a capacidade de induzir morte celular em diversas linhagens celulares. Portanto, este trabalho relata as características de morte celular dos oxisteróis 7-cetocolesterol (7-KC), colestane-3Beta-5Alfa-6Beta-triol (Triol), 3,5 colestane-7-ona (Colestona), 3Alfa-5Beta-6Alfa-colestane-3,6-diol (Diol), acetato de colesterol (Acetato), 7-oxocolesterol-5-em-3-beta-il-acetato (7-oxo), 5Beta-6Beta epoxicolesterol (Epoxi) em CTM de indivíduos portadores de LMA. Os resultados indicaram que os oxisteróis 7-KC e Triol tiveram efeitos citotóxicos promovendo a morte celular. O 7-KC foi avaliado em relação aos mecanismos de sua citotoxicidade, gerando aumento de ROS, apoptose e autofagia de modo dose-dependente, o que explica pelo menos em parte, seu efeito citotóxico. Desse modo, o 7-KC apresenta potencial efeito como adjuvante terapêuticoAcute myeloid leukemia (AML) is a neoplasm that affects maturation of hematopoietic stem cells (HSC), compromising the production of healthy bone marrow components. AML affects people of all ages and the survival rates of individuals with the disease are still low. Several studies report the interaction of mesenchymal stem cells (MSC) in the regulation and maintenance of HSC. MSC can secrete mediators in the microenvironment that are involved in the malignancy of hematological tumors. Thus, new forms of therapeutic adjuvants in the fight against cancer are essential. As an adjuvant treatment, studies have shown that substances such as oxisterols, which are oxidized compounds of cholesterol, have the ability to induce cell death in several cell lines. Therefore, this paper reports the cell death characteristics of oxisterols. 7-ketocholesterol (7-KC), cholestane-3Beta-5Alpha-6Beta-triol (Triol), 3,5-cholestane-7-one (Cholestone), 3Alpha-5Beta -6Alpha-cholestane-3,6-diol (Diol), cholesteryl acetate (Acetate), 7-oxocolesterol-5-em-3-beta-yl-acetate (7-oxo), 5Beta-6Beta epoxycholesterol (Epoxy) in MSC of individuals with AML. The results indicated that 7-KC and Triol oxysterols had cytotoxic effects promoting cell death. Further, 7-KC was evaluated in relation to the mechanisms of cytotoxicity. It led to ROS increase, apoptosis and autophagy in a dose-dependent manner, which explains, at least in part, the observed cytotoxic effect. Thus, 7-KC is a potential therapeutic adjuvant in the treatment of this diseas

7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia

7-Ketocholesterol (7-KC) is a cholesterol oxidation product with several biological functions. 7-KC has the capacity to cause cell death depending on the concentration and specific cell type. Mesenchymal stem cells (MSCs) are multipotent cells with the ability to differentiate into various types of cells, such as osteoblasts and adipocytes, among others. MSCs contribute to the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases, such as leukemia, to a yet unknown extent. Here, we describe the effect of 7-KC on the death of bone marrow MSCs from patients with acute myeloid leukemia (LMSCs). LMSCs were less susceptible to the death-promoting effect of 7-KC than other cell types. 7-KC exposure triggered the extrinsic pathway of apoptosis with an increase in activated caspase-8 and caspase-3 activity. Mechanisms other than caspase-dependent pathways were involved. 7-KC increased ROS generation by LMSCs, which was related to decreased cell viability. 7-KC also led to disruption of the cytoskeleton of LMSCs, increased the number of cells in S phase, and decreased the number of cells in the G1/S transition. Autophagosome accumulation was also observed. 7-KC downregulated the SHh protein in LMSCs but did not change the expression of SMO. In conclusion, oxiapoptophagy (OXIdative stress + APOPTOsis + autophagy) seems to be activated by 7-KC in LMSCs. More studies are needed to better understand the role of 7-KC in the death of LMSCs and the possible effects on the SHh pathway