The mechanism of brigatinib-induced adverse reactions: Study of immunostimulatory effects using THP-1 cells

<p>Background</p><p>Brigatinib (BRG) have been reported to cause hepatic dysfunction-related events, some of which are serious. Idiosyncratic drug-induced liver injury is often immune-mediated and triggered by drugs or their reactive metabolites. BRG contains a piperazine ring and produces iminium derivatives, which are reactive metabolites, in the process of metabolism.However, it is unknown whether BRG and its reactive metabolites activate immune system.</p><p>In this study, we examined that BRG and its reactive metabolites can activate inflammasomes of THP-1 cells for the purpose of assessing immune system activation.</p><p>Methods</p><p>Differentiated THP-1 cells were incubated with BRG (0.3-3 μM) for 24 hours. FLC-4 cells cultured in 3D incubated with BRG (0.3-3 μM) for 7 days. The supernatant of culture medium of FLC-4 cells was added to differentiated THP-1 cells and cultured for 24 h. 1-aminobenzotriazole (ABT, 1 mM) was used to inhibit cytochromes P450 and YVAD (1 μM) was used to inhibit caspase-1 activity. IL-1β in differentiated THP-1 cells was measured using an ELISA kit. Caspase-1 activity in differentiated THP-1 cells was measured using the Caspase-Glo 1 Inflammasome Assay.</p><p>Results and Discussion</p><p>Incubation of differentiated THP-1 cells with BRG increased the production of IL-1β and caspase-1 activity. Furthermore, incubation of differentiated THP-1 cells with the supernatant from an incubation of FLC-4 cells with BRG increased the production of IL-1β and caspase-1 activity.On the other hand, the increase of the production of IL-1β by BRG was inhibited by adding YVAD to the vulture medium of the THP-1 cells. </p><p>These results revealed that BRG within the therapeutic range directly activates the inflammasome of THP-1 cells, whitch suggested that immune activation was involved as a mechanism for the development of BRG induced adverse reactions.</p>