Upregulated Wnt/β-catenin signaling is associated with increased cancer cell resistance and cancer cell-elicited immunosuppression. In non-neoplastic immune cells, upregulated Wnt/β-catenin is, however, associated with either immunosuppression or immunostimulation. Therefore, it is difficult to predict the therapeutic impact inhibitors of Wnt/β-catenin signaling will have when combined with cancer immunotherapy. Here, we evaluated the benefit(s) of the Wnt/β-catenin signaling inhibitor XAV939 in the in vitro elimination of LNCaP prostate cancer cells when cocultured with lymphocytes from patients with localized biochemically recurrent prostate cancer (BRPCa). We found that 5 µM XAV939 inhibited β-catenin translocation to the nucleus in LNCaP cells and CD4+ BRPCa lymphocytes without affecting their proliferation and viability. Preconditioning BRPCa lymphocytes with 5 µM XAV939 accelerated the elimination of LNCaP cells during the coculturing. However, during subsequent re-coculturing with fresh LNCaP cells, BRPCa lymphocytes were no longer able to eliminate LNCaP cells unless coculturing and re-coculturing were performed in the presence of 5 µM XAV939. Comparable results were obtained for PC-3 prostate cancer cells. These findings provide a rationale for combining cell-based immunotherapy of PCa with inhibitors of Wnt/β-catenin signaling.
- MeSH
- beta-katenin antagonisté a inhibitory metabolismus MeSH
- buňky PC-3 MeSH
- CD4-pozitivní T-lymfocyty účinky léků imunologie MeSH
- heterocyklické sloučeniny tricyklické farmakologie MeSH
- imunoterapie metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty farmakoterapie genetika patologie MeSH
- proteiny Wnt antagonisté a inhibitory metabolismus MeSH
- protinádorové látky farmakologie MeSH
- senioři MeSH
- signální dráha Wnt účinky léků MeSH
- T-lymfocyty cytologie imunologie MeSH
- tankyrasy antagonisté a inhibitory MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- dolutegravir,
- MeSH
- antivirové látky aplikace a dávkování farmakologie škodlivé účinky terapeutické užití MeSH
- heterocyklické sloučeniny tricyklické * aplikace a dávkování farmakologie škodlivé účinky terapeutické užití MeSH
- HIV infekce * farmakoterapie MeSH
- hodnocení léčiv statistika a číselné údaje MeSH
- inhibitory HIV-integrasy * farmakologie škodlivé účinky terapeutické užití MeSH
- léková rezistence MeSH
- lékové interakce MeSH
- lidé MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers. Submitted: 17. 11. 2014 Accepted: 29. 11. 2014
- MeSH
- adherence k farmakoterapii MeSH
- akutní nemoc MeSH
- antivirové látky aplikace a dávkování klasifikace kontraindikace terapeutické užití MeSH
- chronická hepatitida C * diagnóza genetika prevence a kontrola přenos terapie MeSH
- genotyp MeSH
- hepatitida C - protilátky diagnostické užití MeSH
- hepatitida C epidemiologie MeSH
- heterocyklické sloučeniny tricyklické farmakologie MeSH
- interferon alfa farmakologie MeSH
- jaterní cirhóza farmakoterapie MeSH
- kombinovaná farmakoterapie MeSH
- lidé MeSH
- nemoci jater diagnóza patologie MeSH
- oligopeptidy farmakologie MeSH
- polyethylenglykoly farmakologie MeSH
- prolin analogy a deriváty farmakologie MeSH
- protilátky virové izolace a purifikace MeSH
- transplantace jater MeSH
- uridinmonofosfát analogy a deriváty MeSH
- uživatelé drog MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Most studies describing phenotypic resistance to integrase strand transfer inhibitors have analyzed viruses carrying only patient-derived HIV-1 integrase genes (INT-recombinant viruses). However, to date, many of the patients on INSTI-based treatment regimes, such as raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) are infected with multidrug-resistant HIV-1 strains. Here we analyzed the effect of drug resistance mutations in Gag (p2/NCp7/p1/p6), protease (PR), reverse transcriptase (RT), and integrase (IN) coding regions on susceptibility to INSTIs and viral replicative fitness using a novel HIV-1 phenotyping assay. Initial characterization based on site-directed mutant INSTI-resistant viruses confirmed the effect of a series of INSTI mutations on reduced susceptibility to EVG and RAL and viral replicative fitness (0.6% to 99% relative to the HIV-1NL4-3 control). Two sets of recombinant viruses containing a 3,428-bp gag-p2/NCp7/p1/p6/pol-PR/RT/IN (p2-INT) or a 1,088 bp integrase (INT) patient-derived fragment were constructed from plasma samples obtained from 27 virologic failure patients participating in a 48-week dose-ranging study of elvitegravir, GS-US-183-0105. A strong correlation was observed when susceptibility to EVG and RAL was assayed using p2-INT- vs. INT-recombinant viruses (Pearson coefficient correlation 0.869 and 0.918, P<0.0001 for EVG and RAL, respectively), demonstrating that mutations in the protease and RT have limited effect on susceptibility to these INSTIs. On the other hand, the replicative fitness of viruses harboring drug resistance mutations in PR, RT, and IN was generally impaired compared to viruses carrying only INSTI-resistance mutations. Thus, in the absence of drug pressure, drug resistance mutations in the PR and RT contribute to decrease the replicative fitness of the virus already impaired by mutations in the integrase. The use of recombinant viruses containing most or all HIV-1 regions targeted by antiretroviral drugs might be essential to understand the collective effect of epistatic interactions in multidrug-resistant viruses.
- MeSH
- antiretrovirové látky farmakologie MeSH
- buněčné linie MeSH
- chinolony farmakologie MeSH
- heterocyklické sloučeniny tricyklické farmakologie MeSH
- HIV-1 účinky léků genetika MeSH
- inhibitory HIV-integrasy farmakologie MeSH
- integrasy genetika MeSH
- lidé MeSH
- mutace MeSH
- pyrrolidinony farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.
- MeSH
- akridiny chemická syntéza chemie farmakologie MeSH
- Alzheimerova nemoc farmakoterapie enzymologie MeSH
- butyrylcholinesterasa chemie farmakologie MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- cholinesterasy chemie MeSH
- heterocyklické sloučeniny tricyklické chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- preklinické hodnocení léčiv MeSH
- takrin chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
