Centrations (19). MKC1 encodes the central kinase in the C. albicans cell
Centrations (19). MKC1 encodes the central kinase on the C. albicans cell wall integrity (CWI) pathway (20). We previously showed that OSIP108 ALK1 drug activates the C. albicans cell wall integrity pathway (14). Nevertheless, such a paradoxical biofilm impact was not observed for the native OSIP108. It remains to be elucidated regardless of whether the OSIP108 analogues that induce this paradoxical development phenomenon in C. albicans biofilm cells induce the CWI pathway 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 considerably alter the antibiofilm activity of OSIP108. Subsequent double and triple combinations of analogues with enhanced antibiofilm activities allowed us to select OSIP108 with Q6RG7K as the tested analogue with highest antibiofilm possible, with an 8.1-fold-higher activity against C. albicans biofilms. In view with the urgent clinical require for novel and more useful antibiofilm treatment options, the OSIP108 variants with improved antibiofilm activities are valuable antibiofilm lead molecules.ACKNOWLEDGMENTSThis function was supported by the European Commission’s Seventh Framework Programme (FP72007-2013) beneath grant agreement COATIM (project number 278425), Fonds Wetenschappelijk Onderzoek (FWO)– Vlaanderen (G.0414.09, W0.026.11N, and K220313N), Agentschap voor Innovatie door CXCR4 Purity & Documentation Wetenschap en Technologie (IWT)–Vlaanderen (SBO grant 120005), KU Leuven (information platform IOFKP11007), and Bijzonder Onderzoeksfonds KU Leuven (GOA200811). Moreover, this work was supported by the Industrial Investigation 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 Investigation Council Professorial Fellowship (APP1026501 and APP1028509, to D.J.C.), and the National Institute of Allergy and Infectious Ailments (R01AI081794, to C.A.K.).
Ebert et al. Molecular Cancer 2014, 13:265 http:molecular-cancercontent131RESEARCHOpen 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 utilised for the remedy of osteoporosis and bone metastases. Clinical studies indicated a advantage in survival and tumor relapse in subpopulations of breast cancer individuals getting zoledronic acid, as a result stimulating the debate about its anti-tumor activity. Amino-bisphosphonates in nM concentrations inhibit farnesyl pyrophosphate synthase major to accumulation of isopentenyl pyrophosphate (IPP) plus the ATP pyrophosphate adduct ApppI, which induces apoptosis in osteoclasts. For anti-tumor effects M concentrations are needed plus a sensitizer for bisphosphonate effects could be beneficial in clinical anti-tumor applications. We hypothesized that enhancing intracellular pyrophosphate accumulation by means of inhibition of probenecid-sensitive channels and transporters would sensitize tumor cells for bisphosphonates anti-tumor efficacy. Solutions: MDA-MB-231, T47D and MCF-7 breast cancer cells were treated with BP (zoledronic acid, risedronate, ibandronate, alendronate) along with the pyrophosphate channel inhibitors probenecid and novobiocin. We determined cell viability and caspa.
