[HTML][HTML] Cyclophosphamide induces an early wave of acrolein-independent apoptosis in the urothelium
FM Hughes Jr, AG Corn, AR Nimmich… - … in bioscience and …, 2013 - ncbi.nlm.nih.gov
FM Hughes Jr, AG Corn, AR Nimmich, JD Pratt-Thomas, JT Purves
Advances in bioscience and biotechnology (Print), 2013•ncbi.nlm.nih.govPurpose Hemorrhagic cystitis (HC or bladder inflammation) affects a significant number of
patients undergoing cyclophosphamide (CP) chemotherapy despite treatment with 2-
mercaptoethane sulfonate (Mesna) to inactivate the metabolite acrolein. While the
mechanism is unknown, there is clearly acrolein-independent damage to the urothelium. In
this study we have explored the induction of apoptosis in the urothelium as a marker of
damage and the mechanism underlying the acrolein-independent apoptosis. Materials and …
patients undergoing cyclophosphamide (CP) chemotherapy despite treatment with 2-
mercaptoethane sulfonate (Mesna) to inactivate the metabolite acrolein. While the
mechanism is unknown, there is clearly acrolein-independent damage to the urothelium. In
this study we have explored the induction of apoptosis in the urothelium as a marker of
damage and the mechanism underlying the acrolein-independent apoptosis. Materials and …
Abstract
Purpose
Hemorrhagic cystitis (HC or bladder inflammation) affects a significant number of patients undergoing cyclophosphamide (CP) chemotherapy despite treatment with 2-mercaptoethane sulfonate (Mesna) to inactivate the metabolite acrolein. While the mechanism is unknown, there is clearly acrolein-independent damage to the urothelium. In this study we have explored the induction of apoptosis in the urothelium as a marker of damage and the mechanism underlying the acrolein-independent apoptosis.
Materials and Methods
Apoptosis in urothelium (caspase-3/7 activity and Poly (ADP-ribosyl) polymerase (PARP) cleavage) was measured following CP administration (80 mg/kg). Sodium 2-mercaptoethane sulfonate (Mesna) was used to mask acrolein’s effect. An IL-1β receptor antagonist and a cell-permeable caspase-1 inhibitor were used to assess the involvement of IL-1β and caspase-1, respectively.
Results
Two waves of apoptosis were detected following CP administration, one peaking at 2 h and a second at 48 h. The first wave was independent of acrolein. Caspase-1 was also active at 2 h and activation of caspase-3/7 was blocked by a caspase-1 inhibitor but not an IL-1β receptor antagonist suggesting the direct activation of caspase-3/7 by caspase-1 without the need for IL-1β as an intermediate.
Conclusions
Our results indicate that CP initiates an early, acrolein-independent wave of apoptosis that results from direct cleavage of caspase-3/7 by caspase-1.
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