Fig. 8.

A schematic of how PDE5 inhibitors and DNA damaging drugs interact to kill T24 cells. PDE5 inhibitors such as sildenafil inhibit PDE5, which leads to increased cGMP levels, increased iNOS expression, and elevated levels of NO. DNA damaging drugs stimulate the production of ROS that is counteracted by ATM. ROS and NO generate peroxynitrite, which inhibits the protein tyrosine phosphatase that inhibits CD95. CD95 becomes activated, stimulating (1) the extrinsic apoptosis pathway and (2) through RIP-1, an autophagy pathway that also leads to cell killing. BID, BH3 interacting-domain death agonist.