Open AccessThe new low‐toxic histone deacetylase inhibitor S ‐(2) induces apoptosis in various acute myeloid leukaemia cells
Author(s) -
Cellai C.,
Balliu M.,
Laurenzana A.,
Guandalini L.,
Matucci R.,
Miniati D.,
Torre E.,
Nebbioso A.,
Carafa V.,
Altucci L.,
Romanelli M. N.,
Paoletti F.
Publication year - 2012
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2011.01464.x
Subject(s) - histone deacetylase , cancer research , apoptosis , cell cycle , biology , cell cycle checkpoint , cell growth , myeloid , acetylation , microbiology and biotechnology , cyclin d3 , histone , cyclin , biochemistry , dna , gene
Histone deacetylase inhibitors (HDACi) induce tumour cell cycle arrest and/or apoptosis, and some of them are currently used in cancer therapy. Recently, we described a series of powerful HDACi characterized by a 1,4‐benzodiazepine (BDZ) ring hybridized with a linear alkyl chain bearing a hydroxamate function as Zn ++ ‐chelating group. Here, we explored the anti‐leukaemic properties of three novel hybrids, namely the chiral compounds (S) ‐ 2 and (R) ‐ 2 , and their non‐chiral analogue 4 , which were first comparatively tested in promyelocytic NB4 cells. (S) ‐ 2 and partially 4 – but not (R) ‐ 2 – caused G0/G1 cell‐cycle arrest by up‐regulating cyclin G2 and p21 expression and down‐regulating cyclin D2 expression, and also apoptosis as assessed by cell morphology and cytofluorimetric assay, histone H2AX phosphorylation and PARP cleavage. Notably, these events were partly prevented by an anti‐oxidant. Moreover, novel HDACi prompted p53 and α‐tubulin acetylation and, consistently, inhibited HDAC1 and 6 activity. The rank order of potency was (S) ‐ 2 > 4 > (R) ‐ 2 , reflecting that of other biological assays and addressing (S) ‐ 2 as the most effective compound capable of triggering apoptosis in various acute myeloid leukaemia (AML) cell lines and blasts from patients with different AML subtypes. Importantly, (S) ‐ 2 was safe in mice (up to 150 mg/kg/week) as determined by liver, spleen, kidney and bone marrow histopathology; and displayed negligible affinity for peripheral/central BDZ‐receptors. Overall, the BDZ‐hydroxamate (S) ‐ 2 showed to be a low‐toxic HDACi with powerful anti‐proliferative and pro‐apototic activities towards different cultured and primary AML cells, and therefore of clinical interest to support conventional anti‐leukaemic therapy.