title: The cytotoxic activity of Aplidin in chronic lymphocytic leukemia (CLL) is mediated by a direct effect on leukemic cells and an indirect effect on monocyte-derived cells.
abstract: Aplidin is a novel cyclic depsipeptide, currently in Phase II/III clinical trials for solid and hematologic malignancies. The aim of this study was to evaluate the effect of Aplidin in chronic lymphocytic leukemia (CLL), the most common leukemia in the adult. Although there have been considerable advances in the treatment of CLL over the last decade, drug resistance and immunosuppression limit the use of current therapy and warrant the development of novel agents. Here we report that Aplidin induced a dose- and time-dependent cytotoxicity on peripheral blood mononuclear cells (PBMC) from CLL patients. Interestingly, Aplidin effect was markedly higher on monocytes compared to T lymphocytes, NK cells or the malignant B-cell clone. Hence, we next evaluated Aplidin activity on nurse-like cells (NLC) which represent a cell subset differentiated from monocytes that favors leukemic cell progression through pro-survival signals. NLC were highly sensitive to Aplidin and, more importantly, their death indirectly decreased neoplasic clone viability. The mechanisms of Aplidin-induced cell death in monocytic cells involved activation of caspase-3 and subsequent PARP fragmentation, indicative of death via apoptosis. Aplidin also showed synergistic activity when combined with fludarabine or cyclophosphamide. Taken together, our results show that Aplidin affects the viability of leukemic cells in two different ways: inducing a direct effect on the malignant B-CLL clone; and indirectly, by modifying the microenvironment that allows tumor growth.
authors: Laboratory of Immunology, IIHEMA, National Academy of Medicine, Buenos Aires, Argentina.
authors: Pablo E
authors: PE
authors: Morande
authors: Samanta R
authors: SR
authors: Zanetti
authors: Mercedes
authors: M
authors: Borge
authors: Paula
authors: P
authors: Nannini
authors: Carolina
authors: C
authors: Jancic
authors: Raimundo F
authors: RF
authors: Bezares
authors: Alicia
authors: A
authors: Bitsmans
authors: Miguel
authors: M
authors: González
authors: Andrea L
authors: AL
authors: Rodríguez
authors: Carlos M
authors: CM
authors: Galmarini
authors: Romina
authors: R
authors: Gamberale
authors: Mirta
authors: M
authors: Giordano
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage; D047630:Depsipeptides / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D010456:Peptides, Cyclic; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D047630:Depsipeptides; D010456:Peptides, Cyclic; D017382:Reactive Oxygen Species; D003520:Cyclophosphamide; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D014740:Vidarabine; C024352:fludarabine; C098980:plitidepsin