title: Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias.
abstract: Effective inhibition of BCR-ABL tyrosine kinase activity with Imatinib represents a breakthrough in the treatment of patients with chronic myeloid leukemia (CML). However, more than 30 % of patients with CML in chronic phase do not respond adequately to Imatinib and the drug seems not to affect the quiescent pool of BCR-ABL positive leukemic stem and progenitor cells. Therefore, despite encouraging clinical results, Imatinib can still not be considered a curative treatment option in CML. We recently reported downregulation of eukaryotic initiation factor 5A (eIF5A) in Imatinib treated K562 cells. Furthermore, the inhibition of eIF5A by siRNA in combination with Imatinib has been shown to exert synergistic cytotoxic effects on BCR-ABL positive cell lines. Based on the structure of known deoxyhypusine synthase (DHS) inhibitors such as CNI-1493, a drug design approach was applied to develop potential compounds targeting DHS. Here we report the biological evaluation of selected novel (DHSI-15) as compared to established (CNI-1493, deoxyspergualin) DHS inhibitors. We show that upon the compounds tested, DHSI-15 and deoxyspergualin exert strongest antiproliferative effects on BCR-ABL cells including Imatinib resistant mutants. However, this effect did not seem to be restricted to BCR-ABL positive cell lines or primary cells. Both compounds are able to induce apoptosis/necrosis during long term incubation of BCR-ABL positive BA/F3 derivates. Pharmacological synergism can be observed for deoxyspergualin and Imatinib, but not for DHSI-15 and Imatinib. Finally we show that deoxyspergualin is able to inhibit proliferation of CD34+ progenitor cells from CML patients. We conclude that inhibition of deoxyhypusine synthase (DHS) can be supportive for the anti-proliferative treatment of leukemia and merits further investigation including other cancers.
authors.affiliation: Klinik für Onkologie, Hämatologie und Stammzelltransplantation, Universitätsklinikum der RWTH, Aachen University, Aachen, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Ziegler
authors.forename: Tuhama
authors.initials: T
authors.lastname: Chahoud
authors.forename: Thomas
authors.initials: T
authors.lastname: Wilhelm
authors.forename: Nora
authors.initials: N
authors.lastname: Pällman
authors.forename: Melanie
authors.initials: M
authors.lastname: Braig
authors.forename: Valeska
authors.initials: V
authors.lastname: Wiehle
authors.forename: Susanne
authors.initials: S
authors.lastname: Ziegler
authors.forename: Marcus
authors.initials: M
authors.lastname: Schröder
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
authors.forename: Adrian
authors.initials: A
authors.lastname: Kolodzik
authors.forename: Matthias
authors.initials: M
authors.lastname: Rarey
authors.forename: Jens
authors.initials: J
authors.lastname: Panse
authors.forename: Joachim
authors.initials: J
authors.lastname: Hauber
authors.forename: Stefan
authors.initials: S
authors.lastname: Balabanov
authors.forename: Tim H
authors.initials: TH
authors.lastname: Brümmendorf
mesh_terms: D000818:Animals; D018952:Antigens, CD34; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D051379:Mice; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors*; D000813:Anilides
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D006835:Hydrazones; D000587:Oxidoreductases Acting on CH-NH Group Donors; C097256:semapimod; D000813:Anilides; C063507:deoxyhypusine synthase; C037258:gusperimus