STUDIES ON THE EFFECT OF IRINOTECAN ON HMGB1 PROTEIN AS A KEY MEDIATOR IN INFLAMMATION

Introduction: HMGB1 is the most important non-histone protein in chromatin that has key roles in replication, transcription, recombination, and DNA repair inside the cell nucleus. Necrotic or damaged cells, activated monocytes and macrophages secrete this protein into the extracellular space. Extracellular HMGB1 is an important mediator in inducing inflammatory responses and wound healing. Irinotecan as a potent chemotherapy agent exerts its action by binding to DNA-Topo-I complex and prevents rejoining transient DNA breaks, therefore inhibits transcription and replication. In the present study, we focus on the interaction of irinotecan with HMGB1 protein in solution.Method: We have investigated the interaction of irinotecan with HMGB1 in solution employing CD and equilibrium dialysis techniques.Results: The CD results demonstrated the binding of irinotecan to HMGB1 induces structural changes in protein and decreased ellipticity at both 208 and 222 nm extremes. Equilibrium dialysis analysis showed that the binding of the drug to HMGB1 is positive cooperative with association constant (Ka) of 2.44× 102 M−1 and estimation of free energy changes represented exergonic and spontaneous reaction of irinotecan with HMGB1.Discussion: The results demonstrated that irinotecan represents high affinity to HMGB1 providing HMGB1 protein as a new target for irinotecan action.

Keywords:

HMGB1 , irinotecan , inflammation , repair