Abstract

THE IMPACT OF ALPELISIB “PI3K INHIBITOR” ON TNF/NLRP3/IL-1? SIGNALING PATHWAY IN METHOTREXATE-INDUCED HEPATOTOXICITY IN MICE

Rana M. Gamal*, Sara H. Hazem, Rania and R. Abdelaziz

ABSTRACT

Drug-induced liver injury (DILI) is one of the main causes of hepatotoxicity. Chemotherapeutic agents are the most common of these deleterious drug-induced injuries. Methotrexate (MTX), an antimetabolite, is most frequently used as a chemotherapeutic drug for for several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and several types of solid cancer and as an immunosuppressant in autoimmune illness. Since MTX is used so widely, a clear toxicity profile has developed, with hepatotoxicity being the most significant possible side effect. We studied the effect of alpelisib (ALP), a PI3K inhibitor, on the hepatotoxicity induced by methotrexate by targeting the TNF-α/ NLRP3/IL-1β pathway. The mice in this experiment were arbitrarily split into four groups: I) control; II) MTX (20 mg/kg); III) ALP (2.5 mg/kg) + MTX (20 mg/kg) and IV) ALP (5 mg/kg) + MTX (20 mg/kg). Where ALP was administered for 5 days of the experiment and MTX was administered for the last 4 days of the experiment, 2 h after ALP administration. The liver index was estimated via dailyrecording of the body weight changes. In addition, the TNF-α/NLRP3/IL-1β pathway was assessed in liver tissue by ELISA technique. The weight of mice was significantly reduced in MTX group compared to normal control group. On the other hand, liver index was significantly decreased in MTX group only. An evaluation of TNF-α/NLRP3/IL-1β signaling using ELISA showed that this pathway was activated by ALP given in the acute MTX induced hepatotoxicity. Where, ALP induced slight elevation in TNF-α and statistically significant elevation in NLRP3 and IL-1β. In conclusion, our results exclude TNF-

Keywords: ?/NLRP3/IL-1? inflammatory signaling pathway to be involved in PI3K inhibition mediated amelioration of MTX-indued hepatotoxicity.