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Novel second mitochondria-derived activator of caspases (Smac) mimetic compounds sensitize human leukemic cell lines to conventional chemotherapeutic drug-induced and death receptor-mediated apoptosis

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Summary

The Inhibitor of Apoptosis Proteins (IAPs) are important regulators of programmed cell death. XIAP is the most potent among them and is over-expressed in several hematological malignancies. Its activity is endogenously antagonized by SMAC/DIABLO, and also by small molecules mimicking Smac that can induce apoptosis in tumor cells. Here we describe the activity of 56 newly synthesized Smac-mimetics in human leukemic cell lines and normal CD34+ progenitor cells. Our compounds bind to XIAP with high affinity, reduce the levels of cIAP1 and are cytotoxic at nanomolar or low micromolar concentrations. Furthermore, the Smac-mimetics synergize with Cytarabine, Etoposide and especially with TRAIL in combination treatments. Apoptosis activation was clearly detectable by the occurrence of sub G1 apoptotic peak and the accumulation of cleaved PARP, caspase 8 and caspase 3. Interestingly, the down-regulation of XIAP sensitized Jurkat cells to drugs too, confirming the role of this protein in drug-resistance. In conclusion, while being very active in leukemic cells, our Smac-mimetics have modest effects on normal hematopoietic progenitors, suggesting their promising therapeutic potential as a new class of anticancer drugs in onco-hematology, particularly when combined with TRAIL, to overcome the resistance of cancer cells.

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Acknowledgements

We thank Professor Henning Walczak, Imperial College, London, UK for providing IZ TRAIL and Dr H. Kashkar, Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Germany for providing lentiviral vectors.

This work was partially supported by Associazione Italiana contro le Leucemie, Linfomi e Mieloma (AIL), sezione di Milano, Milan, Italy and in part by grants from Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR, Rome, Italy), Alleanza Contro il Cancro (Rome, Italy), and Michelangelo Foundation for Advances in Cancer Research and Treatment (Milano, Italy) to CC-S.

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Authors and Affiliations

  1. Fondazione Matarelli, Dipartimento di Farmacologia Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129, Milan, Italy

    Federica Servida, Cinzia Scavullo, Elio Polli, Giorgio Lambertenghi Deliliers & Francesco Onida

  2. Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Daniele Lecis & Domenico Delia

  3. Centro Interdisciplinare di Studi Biomolecolari e Applicazioni Industriali (CISI), Milan, Italy

    Carmelo Drago, Pierfausto Seneci & Leonardo Manzoni

  4. Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Milan, Italy

    Pierfausto Seneci

  5. CNR–Istituto di Scienze e Tecnologie Molecolari, Milan, Italy

    Leonardo Manzoni

  6. Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori and University of Milano, Milan, Italy

    Carmelo Carlo-Stella

  7. U.O. Ematologia 1- CTMO, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano, Milan, Italy

    Giorgio Lambertenghi Deliliers & Francesco Onida

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  1. Federica Servida
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  2. Daniele Lecis
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  3. Cinzia Scavullo
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  9. Giorgio Lambertenghi Deliliers
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  10. Domenico Delia
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Correspondence to Federica Servida.

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Domenico Delia and Francesco Onida contributed equally to this work.

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Servida, F., Lecis, D., Scavullo, C. et al. Novel second mitochondria-derived activator of caspases (Smac) mimetic compounds sensitize human leukemic cell lines to conventional chemotherapeutic drug-induced and death receptor-mediated apoptosis. Invest New Drugs 29, 1264–1275 (2011). https://doi.org/10.1007/s10637-010-9475-6

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