TY - JOUR
T1 - 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
AU - Morande, Pablo E.
AU - Zanetti, Samanta R.
AU - Borge, Mercedes
AU - Nannini, Paula
AU - Jancic, Carolina
AU - Bezares, Raimundo F.
AU - Bitsmans, Alicia
AU - González, Miguel
AU - Rodríguez, Andrea L.
AU - Galmarini, Carlos M.
AU - Gamberale, Romina
AU - Giordano, Mirta
N1 - Funding Information:
Acknowledgements The authors would like to thank all patients and donors for their participation in this study; Dr Analía Trevani for assistance with fluorescence microscopy; Ms Beatriz Loria and Ms Mabel Horvat for technical assistance. This work was supported by grants from Agencia Nacional de Promoción Científica (Argentina), CONICET and Fundación Florencio Fiorini.
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
KW - Aplidin
KW - Chronic lymphocytic leukemia
KW - Monocytes
KW - Myeloid cells
KW - Plitidepsin
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=84867877192&partnerID=8YFLogxK
U2 - 10.1007/s10637-011-9740-3
DO - 10.1007/s10637-011-9740-3
M3 - Article
C2 - 21887502
AN - SCOPUS:84867877192
SN - 0167-6997
VL - 30
SP - 1830
EP - 1840
JO - Investigational New Drugs
JF - Investigational New Drugs
IS - 5
ER -