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.