The novel proapoptotic activity of nonnatural enantiomer of Lentiginosine.
D-(-)-Lentiginosine [(-)-4], the nonnatural enantiomer of the iminosugar indolizidine alkaloid L-(+)-lentiginosine, acts as apoptosis inducer on tumor cells of different origin, in contrast to its natural enantiomer. Although D-(-)-4 exhibited a proapoptotic activity towards tumor cells at level lower than the chemotherapeutic agent, SN38, it was less proapoptotic towards normal cells and less cytotoxic. Apoptosis induced by D-(-)-4 was caspase-dependent, as shown by the increased expression and activity of caspase-3 and -8 in treated cells, and by inhibition following treatment with the pan caspase inhibitor, ZVAD-FMK. This study highlighted how a natural iminosugar alkaloid and its synthetic enantiomer, which were simply known for their inhibition against a fungal glucoamylase, could behave in a complete different way when tested towards cell growth and death of cells of different origin.
Macchi
Beatrice
B
Department of Neuroscience, University of Rome Tor Vergata Via Montpellier 1 Rome 00133 and IRCCS S. Lucia, Via Ardeatina 300 00100 Rome, Italy. macchi@med.uniroma2.it
Minutolo
Antonella
A
Grelli
Sandro
S
Cardona
Francesca
F
Cordero
Franca M
FM
Mastino
Antonio
A
Brandi
Alberto
A
D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D053148:Caspase 3 / Q000096:biosynthesis / Q000378:metabolism; D053181:Caspase 8 / Q000096:biosynthesis / Q000378:metabolism; D061945:Caspase Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005087:Glucan 1,4-alpha-Glucosidase / Q000037:antagonists & inhibitors; D006801:Humans; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C106003:SN38-Glu; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C063984:lentiginosine; D005087:Glucan 1,4-alpha-Glucosidase; D053148:Caspase 3; D053181:Caspase 8; D002166:Camptothecin