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

MORANDE PABLO; ZANETTI SAMANTA ROMINA; BORGE MERCEDES; NANNINI PAULA ROMINA; JANCIC CAROLINA; BEZARES RAIMUNDO FERNANDO; BISTMANS ALICIA; GONZALEZ MIGUEL; RODRIGUEZ ANDREA; CARLOS GALMARINI; GAMBERALE ROMINA; GIORDANO MIRTA

INVESTIGATIONAL NEW DRUGS

SPRINGER

Lugar: Berlin; Año: 2012 vol. 30 p. 1830 - 1840

0167-6997

Summary Aplidin is a novel cyclic depsipeptide, currentlyin Phase II/III clinical trials for solid and hematologicmalignancies. The aim of this study was to evaluate theeffect of Aplidin in chronic lymphocytic leukemia (CLL),the most common leukemia in the adult. Although therehave been considerable advances in the treatment of CLLover the last decade, drug resistance and immunosuppressionlimit the use of current therapy and warrant thedevelopment of novel agents. Here we report that Aplidininduced a dose- and time-dependent cytotoxicity onperipheral blood mononuclear cells (PBMC) from CLLpatients. Interestingly, Aplidin effect was markedly higheron monocytes compared to T lymphocytes, NK cells or themalignant B-cell clone. Hence, we next evaluated Aplidinactivity on nurse-like cells (NLC) which represent a cellsubset differentiated from monocytes that favors leukemiccell progression through pro-survival signals. NLC werehighly sensitive to Aplidin and, more importantly, theirdeath indirectly decreased neoplasic clone viability. Themechanisms of Aplidin-induced cell death in monocyticcells involved activation of caspase-3 and subsequent PARPfragmentation, indicative of death via apoptosis. Aplidinalso showed synergistic activity when combined withfludarabine or cyclophosphamide. Taken together, ourresults show that Aplidin affects the viability of leukemiccells in two different ways: inducing a direct effect on themalignant B-CLL clone; and indirectly, by modifying themicroenvironment that allows tumor growth.