RESUMEN
Anaplastic thyroid cancer (ATC) is an aggressive form of thyroid cancer (TC), accounting for 50% of total TC-related deaths. Although therapeutic approaches against TC have improved in recent years, the survival rate remains low, and severe adverse effects are commonly reported. However, unexplored alternatives based on natural compounds, such as lysicamine, an alkaloid found in plants with established cytotoxicity against breast and liver cancers, offer promise. Therefore, this study aimed to explore the antineoplastic effects of lysicamine in papillary TC (BCPAP) and ATC (HTH83 and KTC-2) cells. Lysicamine treatment reduced cell viability, motility, colony formation, and AKT activation while increasing the percentage of necrotic cells. The absence of caspase activity confirmed apoptosis-independent cell death. Necrostatin-1 (NEC-1)-mediated necrosome inhibition reduced lysicamine-induced necrosis in KTC-2, suggesting necroptosis induction via a reactive oxygen species (ROS)-independent mechanism. Additionally, in silico analysis predicted lysicamine target proteins, particularly those related to MAPK and TGF-ß signaling. Our study demonstrated lysicamine's potential as an antineoplastic compound in ATC cells with a proposed mechanism related to inhibiting AKT activation and inducing cell death.
RESUMEN
Knowing how a bioactive compound interacts with cell membranes is important to understand its effect at the molecular level. In this sense, this work aimed to study the interaction of lysicamine, an alkaloid with action against lung cancer cell lines, with lipid monolayers as cell membrane models. We employed two lipid mixtures: the first composed of 35% DOPC, 30% DOPE, 20% sphingomyelin, and 15% cholesterol as healthy cell membranes models (MM1), and the second replacing DOPC with DOPS as cancer cells models (MM2). The interaction of lysicamine with the monolayers was evaluated using tensiometry, Brewster angle microscopy (BAM), and polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). Lysicamine had interfacial effects in both membrane models. For MM 1, it expanded the lipid monolayer and changed the interfacial rheological properties, increasing the in-plane elasticity of the films. PM-IRRAS spectra suggested a higher conformational disorder of the alkyl chains of the lipids. For MM 2, lysicamine also shifted the isotherms to higher areas, expanding the monolayers, but with no significant alteration in their interfacial rheological properties. PM-IRRAS spectra also suggested higher disorder in the orientation of the lipid alkyl chains upon lysicamine incorporation. For both models, BAM did not show alteration in interfacial aggregation upon drug incorporation. In conclusion, changes in some interfacial properties of membrane models caused by lysicamine depend on the monolayer composition, which can be associated with its bioactivity in cellular membranes.
