title: Mechanism of the antitumoral activity of deferasirox, an iron chelation agent, on mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) characterized by the t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression, is one of the most challenging lymphomas to treat. Iron chelators, such as deferasirox, have previously been shown to exhibit anti-proliferative properties; however, their effect on MCL cells has never been investigated. We showed that deferasirox exhibited antitumoral activity against the MCL cell lines HBL-2, Granta-519 and Jeko-1, with 50% inhibitory concentration (IC(50)) values of 7.99 ± 2.46 μM, 8.93 ± 2.25 μM and 31.86 ± 7.26 μM, respectively. Deferasirox induced apoptosis mediated through caspase-3 activation and decreased cyclin D1 protein levels resulting from increased proteasomal degradation. We also demonstrated down-regulation of phosphor-RB (Ser780) expression, which resulted in increasing levels of the E2F/RB complex and G(1)/S arrest. Finally, we showed that deferasirox activity was dependent on its iron chelating ability. The present data indicate that deferasirox, by down-regulating cyclin D1 and inhibiting its related signals, may constitute a promising adjuvant therapeutic molecule in the strategy for MCL treatment.
authors.affiliation: Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Vazana-Barad
authors.forename: Galit
authors.initials: G
authors.lastname: Granot
authors.forename: Rahav
authors.initials: R
authors.lastname: Mor-Tzuntz
authors.forename: Itai
authors.initials: I
authors.lastname: Levi
authors.forename: Martin
authors.initials: M
authors.lastname: Dreyling
authors.forename: Ilana
authors.initials: I
authors.lastname: Nathan
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics; D001565:Benzoates / Q000494:pharmacology*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D000077588:Deferasirox; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis; D012333:RNA, Messenger / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001565:Benzoates; D007502:Iron Chelating Agents; D012333:RNA, Messenger; D014230:Triazoles; D019938:Cyclin D1; D007501:Iron; D046988:Proteasome Endopeptidase Complex; D000077588:Deferasirox