TITLE:
Cyclophosphamide induces an early wave of acrolein-independent apoptosis in the urothelium
AUTHORS:
Francis M. Hughes, Alexa G. Corn, Andrew R. Nimmich, Jeffery D. Pratt-Thomas, J. Todd Purves
KEYWORDS:
Cystitis; Cyclophosphamide; Apoptosis; Bladder; Urothelium
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.4 No.8B,
August
8,
2013
ABSTRACT: Hemorrhagic cystitis (HC) 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. Two
waves of apoptosis (measured as caspase-3/7 activity and Poly (ADP-ribosyl) polymerase (PARP) cleavage) were detected following CP administration, one peaking
at 2 h and a second at 48 h. The first wave was not blocked by Mesna, indicating
it 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-1 receptor
antagonist, suggesting the direct activation of caspase-3/7 by caspase-1
without the need for IL-1 as an intermediate. 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.