title: 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.
abstract: 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 G(1) 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.
authors.affiliation: Fondazione Matarelli, Dipartimento di Farmacologia Chemioterapia e Tossicologia Medica, Università degli Studi di Milano, Via Vanvitelli 32, 20129, Milan, Italy. fservida@hotmail.com
authors.forename: Federica
authors.initials: F
authors.lastname: Servida
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecis
authors.forename: Cinzia
authors.initials: C
authors.lastname: Scavullo
authors.forename: Carmelo
authors.initials: C
authors.lastname: Drago
authors.forename: Pierfausto
authors.initials: P
authors.lastname: Seneci
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carlo-Stella
authors.forename: Leonardo
authors.initials: L
authors.lastname: Manzoni
authors.forename: Elio
authors.initials: E
authors.lastname: Polli
authors.forename: Giorgio
authors.initials: G
authors.lastname: Lambertenghi Deliliers
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Francesco
authors.initials: F
authors.lastname: Onida
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D011485:Protein Binding; D013234:Stem Cells / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D051636:X-Linked Inhibitor of Apoptosis Protein; D003561:Cytarabine; D005047:Etoposide