Thway to a higher extent than native OSIP108 and no matter whether this induction on the CWI pathway is accountable for the observed paradoxical biofilm impact. In conclusion, this study shows that site-specific amino acid substitutions can significantly alter the antibiofilm activity of OSIP108. Subsequent double and triple combinations of analogues with improved antibiofilm Aldose Reductase Formulation activities permitted us to choose OSIP108 with Q6R/G7K because the tested analogue with highest antibiofilm prospective, with an eight.1-fold-higher activity against C. albicans biofilms. In view with the urgent clinical need for novel and much more precious antibiofilm remedies, the OSIP108 Neprilysin Inhibitor MedChemExpress variants with improved antibiofilm activities are important antibiofilm lead molecules.ACKNOWLEDGMENTSThis work was supported by the European Commission’s Seventh Framework Programme (FP7/2007-2013) below grant agreement COATIM (project quantity 278425), Fonds Wetenschappelijk Onderzoek (FWO)– Vlaanderen (G.0414.09, W0.026.11N, and K220313N), Agentschap voor Innovatie door Wetenschap en Technologie (IWT)–Vlaanderen (SBO grant 120005), KU Leuven (understanding platform IOF/KP/11/007), and Bijzonder Onderzoeksfonds KU Leuven (GOA/2008/11). Additionally, this function was supported by the Industrial Analysis Fund, KU Leuven (to K.T.), FWO-Vlaanderen (12A7213N and V400314N, to B.D.C.), IWT Flanders (IWT101095, to N.D.), a National Overall health and Health-related Analysis Council Professorial Fellowship (APP1026501 and APP1028509, to D.J.C.), as well as the National Institute of Allergy and Infectious Ailments (R01AI081794, to C.A.K.).
Ebert et al. Molecular Cancer 2014, 13:265 http://molecular-cancer/content/13/1/RESEARCHOpen AccessProbenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cellsRegina Ebert1, Jutta Meissner-Weigl1, Sabine Zeck1, Jorma M tt, Seppo Auriola3, Sofia Coimbra de Sousa3, Birgit Mentrup1, Stephanie Graser1, Tilman D Rachner2, Lorenz C Hofbauer2 and Franz Jakob1AbstractBackground: Anti-resorptive bisphosphonates (BP) are applied for the treatment of osteoporosis and bone metastases. Clinical research indicated a benefit in survival and tumor relapse in subpopulations of breast cancer patients receiving zoledronic acid, therefore stimulating the debate about its anti-tumor activity. Amino-bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase major to accumulation of isopentenyl pyrophosphate (IPP) along with the ATP/ pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti-tumor effects M concentrations are needed along with a sensitizer for bisphosphonate effects could be effective in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation by way of inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy. Methods: MDA-MB-231, T47D and MCF-7 breast cancer cells had been treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) plus the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspase 3/7 activity (apoptosis), accumulation of IPP and ApppI, expression of ANKH, PANX1, ABCC1, SLC22A11, and the zoledronic acid target gene and tumor-suppressor KLF2. Outcomes: Therapy of MDA-MB-231 with BP induced caspase 3/7 activity, with zoledronic acid becoming the most helpful. In MCF-7 and T47D either BP markedly suppressed cell viability with only minor effects on apoptosis. Co-treatment with probenecid enhanced.