The antiproliferative and proapoptotic effects of cladosporols A and B are related to their different binding mode as PPARγ ligands.
Cladosporols are secondary metabolites from Cladosporium tenuissimum characterized for their ability to control cell proliferation. We previously showed that cladosporol A inhibits proliferation of human colon cancer cells through a PPARγ-mediated modulation of gene expression. In this work, we investigated cladosporol B, an oxidate form of cladosporol A, and demonstrate that it is more efficient in inhibiting HT-29 cell proliferation due to a robust G0/G1-phase arrest and p21(waf1/cip1) overexpression. Cladosporol B acts as a PPARγ partial agonist with lower affinity and reduced transactivation potential in transient transfections as compared to the full agonists cladosporol A and rosiglitazone. Site-specific PPARγ mutants and surface plasmon resonance (SPR) experiments confirm these conclusions. Cladosporol B in addition displays a sustained proapoptotic activity also validated by p21(waf1/cip1) expression analysis in the presence of the selective PPARγ inhibitor GW9662. In the DMSO/H2O system, cladosporols A and B are unstable and convert to the ring-opened compounds 2A and 2B. Finally, docking experiments provide the structural basis for full and partial PPARγ agonism of 2A and 2B, respectively. In summary, we report here, for the first time, the structural characteristics of the binding of cladosporols, two natural molecules, to PPARγ. The binding of compound 2B is endowed with a lower transactivation potential, higher antiproliferative and proapoptotic activity than the two full agonists as compound 2A and rosiglitazone (RGZ).
['Zurlo|Diana|D|', 'Ziccardi|Pamela|P|', 'Votino|Carolina|C|', 'Colangelo|Tommaso|T|', 'Cerchia|Carmen|C|', 'Dal Piaz|Fabrizio|F|', 'Dallavalle|Sabrina|S|', 'Moricca|Salvatore|S|', 'Novellino|Ettore|E|', 'Lavecchia|Antonio|A|', 'Colantuoni|Vittorio|V|', 'Lupo|Angelo|A|']
D000813:Anilides D000970:Antineoplastic Agents D017209:Apoptosis D045744:Cell Line, Tumor D049109:Cell Proliferation D050759:Cyclin-Dependent Kinase Inhibitor p21 D054333:Drug Partial Agonism D059585:G1 Phase Cell Cycle Checkpoints D057809:HEK293 Cells D006801:Humans D008024:Ligands D062105:Molecular Docking Simulation D009284:Naphthols D018384:Oxidative Stress D047495:PPAR gamma D011485:Protein Binding D011487:Protein Conformation D013237:Stereoisomerism D013329:Structure-Activity Relationship D015533:Transcriptional Activation
Cladosporols Docking Apoptosis Colorectal cancer cells Full and partial PPARγ agonists