Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias.
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Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias. / Ziegler, Patrick; Chahoud, Tuhama; Wilhelm, Thomas; Pällmann, Nora; Balabanov, Melanie; Wiehle, Valeska; Ziegler, Susanne; Schröder, Marcus; Meier, Chris; Kolodzik, Adrian; Rarey, Matthias; Panse, Jens; Hauber, Joachim; Balabanov, Stefan; Brümmendorf, Tim H.
in: INVEST NEW DRUG, Jahrgang 30, Nr. 6, 6, 2012, S. 2274-2283.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Evaluation of deoxyhypusine synthase inhibitors targeting BCR-ABL positive leukemias.
AU - Ziegler, Patrick
AU - Chahoud, Tuhama
AU - Wilhelm, Thomas
AU - Pällmann, Nora
AU - Balabanov, Melanie
AU - Wiehle, Valeska
AU - Ziegler, Susanne
AU - Schröder, Marcus
AU - Meier, Chris
AU - Kolodzik, Adrian
AU - Rarey, Matthias
AU - Panse, Jens
AU - Hauber, Joachim
AU - Balabanov, Stefan
AU - Brümmendorf, Tim H
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Mice
KW - Cell Line, Tumor
KW - Apoptosis/drug effects
KW - Cell Proliferation/drug effects
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
KW - Antineoplastic Agents/pharmacology
KW - Enzyme Inhibitors/pharmacology
KW - Hydrazones/pharmacology
KW - Antigens, CD34
KW - Guanidines/pharmacology
KW - Oxidoreductases Acting on CH-NH Group Donors/antagonists & inhibitors
KW - Animals
KW - Humans
KW - Mice
KW - Cell Line, Tumor
KW - Apoptosis/drug effects
KW - Cell Proliferation/drug effects
KW - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
KW - Antineoplastic Agents/pharmacology
KW - Enzyme Inhibitors/pharmacology
KW - Hydrazones/pharmacology
KW - Antigens, CD34
KW - Guanidines/pharmacology
KW - Oxidoreductases Acting on CH-NH Group Donors/antagonists & inhibitors
M3 - SCORING: Journal article
VL - 30
SP - 2274
EP - 2283
JO - INVEST NEW DRUG
JF - INVEST NEW DRUG
SN - 0167-6997
IS - 6
M1 - 6
ER -
