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Antitumor activity of methyl (Z)-2-(isothioureidomethyl)-2-pentenoate hydrobromide against leukemia cell lines via mitotic arrest and apoptotic pathways.

Biochimica et biophysica acta. General subjects (2019-06-07)
Laura Sartori Assunção, Iara Fabrícia Kretzer, Jelver Alexander Sierra Restrepo, Leônidas João de Mello Junior, Adny Henrique Silva, Eliana de Medeiros Oliveira, Misael Ferreira, Marcus Mandolesi Sá, Tânia Beatriz Creczynski-Pasa
ABSTRACT

In a previous study, we described a series of 28 aryl- and alkyl-substituted isothiouronium salts with antitumor activity and selectivity toward a leukemia cell line. Among the synthesized compounds, methyl (Z)-2-(isothioureidomethyl)-2-pentenoate hydrobromide (IS-MF08) showed conspicuous activity. In the present study, we investigated the mechanism of action of IS-MF08. Our results showed that its mechanism most likely is related with the membrane receptor Fas and subsequent activation of the extrinsic cell death pathway, triggered by a decrease in the levels of the anti-apoptotic protein Bcl-2 and caspase-8 and -3 cascade activation, causing DNA damage and mitotic arrest. IS-MF08 also caused an increase in intracellular ROS, endoplasmic reticulum (ER) stress, and mitochondrial membrane permeabilization, resulting in organelle degradation as an attempt to reestablish cell homeostasis. Furthermore, cells exposed to IS-MF08 combined to an autophagy inhibitor were less susceptible to compound's cytotoxicity, suggesting that autophagy makes part of its mechanism of action. These data support the hypothesis that IS-MF08 acts by the apoptosis extrinsic pathway and possibly by autophagy as mechanisms of cell death.