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Cyclophosphamide induces an early wave of acrolein-independent apoptosis in the urothelium

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DOI: 10.4236/abb.2013.48A2002    3,906 Downloads   5,074 Views Citations

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.

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Hughes, F. , Corn, A. , Nimmich, A. , Pratt-Thomas, J. and Purves, J. (2013) Cyclophosphamide induces an early wave of acrolein-independent apoptosis in the urothelium. Advances in Bioscience and Biotechnology, 4, 9-14. doi: 10.4236/abb.2013.48A2002.

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