4 research outputs found
Synthesis of Indomorphan Pseudo Natural Product Inhibitors of Glucose Transporters GLUTâ1 and â3
Bioactive compound design based on natural product (NP) structure may be limited due to partial coverage of NPâlike chemical space and biological target space. These limitations can be overcome by combining NPâcentered strategies with fragmentâbased compound design through combination of NPâderived fragments to structurally unprecedented âpseudo natural productsâ (pseudoâNPs). We describe the design, synthesis and biological evaluation of a collection of indomorphan pseudoâNPs that combine biosynthetically unrelated indoleâ and morphanâalkaloid fragments. Biological investigation in a cellâbased screen for modulators of glucose uptake identified the indomorphane derivative Glupin as potent inhibitor of glucose uptake. Glupin selectively targets and upregulates both, glucose transporters GLUTâ1 and GLUTâ3. Glupin suppresses glycolysis, reduces the levels of glucoseâderived metabolites and attenuates the growth of various cancer cell lines. Our findings underscore the importance of dual GLUTâ1 and GLUTâ3 inhibition to efficiently suppress tumor cell growth and the cellular rescue mechanism, which counteracts glucose scarcity
Docetaxel-based induction therapy prior to radiotherapy with or without docetaxel for non-small-cell lung cancer
Glutaminolysis is a metabolic route essential for survival and growth of prostate cancer cells and a target of 5 alpha-dihydrotestosterone regulation
Purpose Resistance to androgen-deprivation therapies and progression to so-called castrate-resistant prostate cancer (CRPC) remain challenges in prostate cancer (PCa) management and treatment. Among other alterations, CRPC has been associated with metabolic reprogramming driven by androgens. Here, we investigated the role of androgens in regulating glutaminolysis in PCa cells and determined the relevance of this metabolic route in controlling the survival and growth of androgen-sensitive (LNCaP) and CRPC (DU145 and PC3) cells. Methods PCa cells (LNCaP, DU145 and PC3) and 3-month old rats were treated with 5 alpha-dihydrotestosterone (DHT). Alternatively, LNCaP cells were exposed to the glutaminase inhibitor BPTES, alone or in combination with the anti-androgen bicalutamide. Biochemical, Western blot and extracellular flux assays were used to evaluate the viability, proliferation, migration and metabolism of PCa cells in response to DHT treatment or glutaminase inhibition. Results We found that DHT up-regulated the expression of the glutamine transporter ASCT2 and glutaminase, both in vitro in LNCaP cells and in vivo in rat prostate cells. BPTES diminished the viability and migration of PCa cells, while increasing caspase-3 activity. CRPC cells were found to be more dependent on glutamine and more sensitive to glutaminase inhibition. BPTES and bicalutamide co-treatment had an additive effect on suppressing LNCaP cell viability. Finally, we found that inhibition of glutaminolysis differentially affected glycolysis and lipid metabolism in both androgen-sensitive and CRPC cells. Conclusion Our data reveal glutaminolysis as a central metabolic route controlling PCa cell fate and highlight the relevance of targeting glutaminase for CRPC treatment.FEDER funds through the POCI - COMPETE 2020 - Operational Programme Competitiveness and Internationalization in Axis I -Strengthening research, technological development and innovation [007491, 029114]; National Funds by the FCT-Foundation for Science and Technology [UID/Multi/00709/2013]; FCTPortuguese Foundation for Science and TechnologyEuropean Commission [SFRH/BD/111351/2015, SFRH/BD/104671/2014, IF/00614/2014/CP12340006]; FCT Investigator contract from the Foundation for Science and Technology (FCT), Portugal [IF/00614/2014]; FCT Research Center gran