Thus, the inhibition of PDE-5 may have anticancer effect. For example, Sarfati and colleagues found that vardenafil could induce the caspase-dependent apoptosis in chronic lymphocytic leukemia cells. This research group also reported that vardenafil, as well as tadalafil, could reverse tumor-induced immunosuppression. In addition vardenafil has been shown to selectively increase the blood-brain tumor barrier permeability by inhibiting ABCB1, thereby enhancing the effects of chemotherapeutic drugs in a mouse metastatic brain tumor model. The current study demonstrates for the first time that vardenafil significantly reverses MDR mediated by the ABCB1 transporter. We also examined the effect of another PDE5 inhibitor, tadalafil, on ABCB1-mediated paclitaxel resistance. In contrast to vardenafil, tadalafil, produced only mild reversal of ABCB1 mediated paclitaxel resistance. One possible explanation for this difference may be related to their structures as the molecular structure of vardenafil is markedly different from that of tadalafil. A number of pharmacophore models for ABCB1 inhibitors have identified features such as hydrophobic interactions, hydrogen bond acceptors, aromatic ring center and positive ionizable groups. Thus, ABCB1 preferentially binds to positively charged, amphipathic molecules and this suggests the involvement of acidic residues such as Asp and Glu in drug binding. Although none of the predicted binding sites of the human ABCB1 transporter have acidic residues, there are a few acidic residues located in a region close to the membrane surface and are accessible from within the drug binding sites. These acidic residues are implicated in providing selectivity towards cationic amphipathic drug molecules through ionic interactions during their entry into the drug binding site of ABCB1. In the present study, vardenafil exhibit all of the pharmacophoric features for interaction with the ABCB1 binding sites, whereas tadalafil lacks the positive ionizable group. Although most of the ABCB1 inhibitors block the function of ABCB1 transporter protein by binding to the substrate binding sites, there is evidence for the presence of multiple binding sites and this hinders the development of a conclusive structure-activity relationship for ABCB1 inhibitors. Until the co-crystal structure studies are performed for the vardenafil-ABCB1 complex, the present docking conformation of vardenafil will serve as a guide for Bortezomib further development of imidazotriazinone class 
of ABCB1 inhibitors. In summary, this is the first study to indicate that the PDE-5 inhibitor, vardenafil, reverses ABCB1-mediated MDR by directly blocking the drug efflux function of ABCB1 without affecting the expression of the transporter. Based on the data presented here, further in vivo studies are warranted to determine if vardenafil can inhibit the ABCB1 transporter and reverse ABCB1-mediated MDR in cancer cells. Fulvestrant serine proteases and serine protease inhibitors, which are found in diverse organisms, are of broad interest because they have diverse physiological functions and affect processes, such as the immune response, hemostasis, fibrinolysis, and the elimination of inflammation. Serine proteases and serine protease inhibitors have been found in snake venom in which many serine proteases exhibit fibrinolytic activity.