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
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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.
KeywordsAplidin Plitidepsin Tumor microenvironment Chronic lymphocytic leukemia Monocytes Myeloid cells
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.
Conflict of interest
C.M. Galmarini: employment, PharmaMar. The other authors reported no potential conflicts of interest.
- 5.Munoz-Alonso MJ, Gonzalez-Santiago L, Martinez T, Losada A, Galmarini CM, Munoz A (2009) The mechanism of action of plitidepsin. In: Current opinion in investigational drugs. 10:536–542Google Scholar
- 6.Le Tourneau C, Faivre S, Ciruelos E, Dominguez MJ, Lopez-Martin JA, Izquierdo MA, Jimeno J, Raymond E (2010) Reports of clinical benefit of plitidepsin (aplidine), a new marine-derived anticancer agent, in patients with advanced medullary thyroid carcinoma. Am J Clin Oncol 33:132–136PubMedGoogle Scholar
- 7.Eisen T, Thomas J, Miller WH, Jr., Gore M, Wolter P, Kavan P, Martin JA, Lardelli P (2009) Phase ii study of biweekly plitidepsin as second-line therapy in patients with advanced malignant melanoma. Melanoma Res 19:185–192. 33Google Scholar
- 8.Mateos MV, Cibeira MT, Richardson PG, Prosper F, Oriol A, de la Rubia J, Lahuerta JJ, Garcia-Sanz R, Extremera S, Szyldergemajn S, Corrado C et al (2010) Phase ii clinical and pharmacokinetic study of plitidepsin 3-hour infusion every two weeks alone or with dexamethasone in relapsed and refractory multiple myeloma. Clin Cancer Res 16:3260–3269PubMedCrossRefGoogle Scholar
- 11.Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grunhagen U, Bergmann M et al (2010) Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376:1164–1174PubMedCrossRefGoogle Scholar
- 21.Fernandez Calotti P, Galmarini CM, Canones C, Gamberale R, Saenz D, Avalos JS, Chianelli M, Rosenstein R, Giordano M (2008) Modulation of the human equilibrative nucleoside transporter1 (hent1) activity by IL-4 and PMA in b cells from chronic lymphocytic leukemia. Biochem Pharmacol 75:857–865PubMedCrossRefGoogle Scholar
- 23.Coscia M, Pantaleoni F, Riganti C, Vitale C, Rigoni M, Peola S, Castella B, Foglietta M, Griggio V, Drandi D, Ladetto M, Bosia A, Boccadoro M, Massaia M (2011) IGHV unmutated CLL B cells are more prone to spontaneous apoptosis and subject to environmental prosurvival signals than mutated CLL B cells. Leukemia 25:828–837PubMedCrossRefGoogle Scholar
- 26.Garcia-Fernandez LF, Losada A, Alcaide V, Alvarez AM, Cuadrado A, Gonzalez L, Nakayama K, Nakayama KI, Fernandez-Sousa JM, Munoz A, Sanchez-Puelles JM (2002) Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated jnk and p38 activation and protein kinase c delta. Oncogene 21:7533–7544PubMedCrossRefGoogle Scholar
- 28.Cuadrado A, Garcia-Fernandez LF, Gonzalez L, Suarez Y, Losada A, Alcaide V, Martinez T, Fernandez-Sousa JM, Sanchez-Puelles JM, Munoz A (2003) Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, src, jnk, and p38 mapk. J Biol Chem 278:241–250PubMedCrossRefGoogle Scholar
- 29.Allavena P, Signorelli M, Chieppa M, Erba E, Bianchi G, Marchesi F, Olimpio CO, Bonardi C, Garbi A, Lissoni A, de Braud F, Jimeno J, D’Incalci M (2005) Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. Cancer Res 65:2964–2971PubMedCrossRefGoogle Scholar
- 31.Germano G, Frapolli R, Simone M, Tavecchio M, Erba E, Pesce S, Pasqualini F, Grosso F, Sanfilippo R, Casali PG, Gronchi A, Virdis E, Tarantino E, Pilotti S, Greco A, Nebuloni M, Galmarini CM, Tercero JC, Mantovani A, D’Incalci M, Allavena P (2010) Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. Cancer Res 70:2235–2244PubMedCrossRefGoogle Scholar