Novel Sildenafil Analogues: Possible Drugs For Increased Sensitivity To Chemotherapuetic Agents | 10497
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The phosphodiesterase 5 (PDE5) inhibitor sildenafil (Viagra ?) also inhibits transport of chemotherapeutic agents out of cancer
cells via human ATP-binding cassette (ABC) transporters. Attempts to develop ABCB1 (P-glycoprotein) inhibitors have
been ongoing for more than 30 years, but because of toxic effects and lack of desired effect of the compounds, none of these
have reached the marked yet. Studies have shown that sildenafil increases the intracellular level of the anticancer agents such
as paclitaxel, 5-fluorouracil, methotrexate, cisplatin, oxaliplatin and doxorubicin by inhibiting a variety of ABC transporters
(ABCB1, ABCC4, ABCC5 and ABCG2), thereby sensitizing cancer cells to these anticancer agents. Furthermore, it has been
shown that several ABC transporters are overexpressed in several types of cancer cells and that sildenafil can inhibit tumor
growth without cytotoxic agents present. We have identified sildenafil analogues using virtual ligand screening (VLS) and tested
them for ABCC5 transporter efflux using inside-out vesicles (IOV). Seven compounds were more potent than sildenafil, and
the two most potent showed K(i) of 50-100 nM. These novel sildenafil analogues may be more effective for inhibiting ABC
transporter efflux, and the side effects may be fewer. However, it is still too early to say whether the sildenafil analogues can
reverse multidrug resistance mediated by ABC-transport in the clinic, but it appears that such compounds may have the potential
to improve the therapeutic results of chemotherapy.
Aina Westrheim Ravna has completed her Ph.D. at the age of 31 years from the University of Troms? and postdoctoral studies from the University
of Troms?, including research stays at the Scripps Research Institute and UCSD, La Jolla, USA. She is currently an Associate Professor at the
University of Troms?. She has more than 30 publications.
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