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

Pablo E. Morande, Samanta R. Zanetti, Mercedes Borge, Paula Nannini, Carolina Jancic, Raimundo F. Bezares, Alicia Bitsmans, Miguel González, Andrea L. Rodríguez, Carlos M. Galmarini, Romina Gamberale, Mirta Giordano*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)

Abstract

Summary: 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.

Original languageEnglish
Pages (from-to)1830-1840
Number of pages11
JournalInvestigational New Drugs
Volume30
Issue number5
DOIs
Publication statusPublished - Oct 2012
Externally publishedYes

Keywords

  • Aplidin
  • Chronic lymphocytic leukemia
  • Monocytes
  • Myeloid cells
  • Plitidepsin
  • Tumor microenvironment

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this