Sildenafil Reverses ABCB1- and ABCG2-Mediated Chemotherapeutic Drug Resistance

Abstract

Sildenafil is a potent and selective inhibitor of the type 5 cGMP (cyclic guanosine 3 0 ,5 0 -monophosphate)-specific phosphodiesterase that is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. Here, we report that sildenafil has differential effects on cell surface ABC transporters such as ABCB1, ABCC1, and ABCG2 that modulate intracompartmental and intracellular concentrations of chemotherapeutic drugs. In ABCB1-overexpressing cells, nontoxic doses of sildenafil inhibited resistance and increased the effective intracellular concentration of ABCB1 substrate drugs such as paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil inhibited resistance to ABCG2 substrate anticancer drugs, for example, increasing the effective intracellular concentration of mitoxantrone or the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of E 2 17bG and methotrexate by the ABCG2 transporter. Mechanistic investigations revealed that sildenafil stimulated ABCB1 ATPase activity and inhibited photolabeling of ABCB1 with [ 125 I]-iodoarylazidoprazosin (IAAP), whereas it only slightly stimulated ABCG2 ATPase activity and inhibited photolabeling of ABCG2 with [ 125 I]-IAAP. In contrast, sildenafil did not alter the sensitivity of parental, ABCB1-, or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drugs, nor did sildenafil affect the function of another ABC drug transporter, ABCC1. Homology modeling predicted the binding conformation of sildenafil within the large cavity of the transmembrane region of ABCB1. Overall, we found that sildenafil inhibits the transporter function of ABCB1 and ABCG2, with a stronger effect on ABCB1. Our findings suggest a possible strategy to enhance the distribution and potentially the activity of anticancer drugs by jointly using a clinically approved drug with known side effects and drug-drug interactions. Cancer Res; 71(8); 3029-41. Ó2011 AACR.

Butorphanol, a synthetic opioid, sensitizes ABCB1-mediated multidrug resistance via inhibition of the efflux function of ABCB1 in leukemia cells

“…1A and B) (33). The results of the MTT assay showed that butorphanol at 4 µM did not restrain the growth of the cells used in the present study.…”

Neratinib Reverses ATP-Binding Cassette B1-Mediated Chemotherapeutic Drug Resistance In Vitro, In Vivo, and Ex Vivo

“…3G61) for site 2 and in an apoprotein state (PDB no. 3G5U) for sites 3 and 4 (Aller et al, 2009), obtained from the Research Collaboratory for Structural Bioinformatics Protein Data Bank (http://www.rcsb.org), were used as the templates to generate homology models for human ABCB1 for sites 1 to 4 (Shi et al, 2011). For evaluation of the possibility of neratinib interacting at the ATP binding site, the crystal structure of the LmrA-ATP binding domain from Lactococcus lactis (PDB no.…”

“…It was reported that ABC transporters acted as modulators of oral absorption, and they have emerged as determinants of sanctuary sites (Shi et al, 2011). A number of blood-tissue barriers, including the blood-brain barrier, the maternalfetal barrier, the blood-testicular barrier, and an apparent blood-cardiac muscle barrier, are mediated at least in part by ABC transporters (Sissung et al, 2011).…”

“…In addition to their roles in protective barriers, ABC transporters decrease the penetration of antineoplastic agents into the targeted tissue compartments. Therefore, identification of agents that block ABC transporters at such sites, leading to increased drug penetration, would have potential clinical benefit well beyond a "reversal of MDR strategy" (Shi et al, 2011).…”

The Role of PDE-5 Inhibitors in Prostate Cancer

“…Recent study showed that the PDE-5 inhibitor, vardenafil, significantly reversed MDR in ABCB1 overexpressing cancer cells, and its efficacy was greater than that of tadalafil (Ding et al, 2011). Sildenafil also inhibited cell surface ABC transporters ABCB1 and ABCG2-midiated drug efflux, resulting in an increase in the intracellular concentrations of anticancer drugs and ensuing drug sensitivity (Shi et al, 2011). However, sildenafil had no effect on efflux mediated by ABCC1.…”