Novel tetra-acridine derivatives as dual inhibitors of topoisomerase II and the human proteasome.
Acridine derivatives, such as amsacrine, represent a well known class of multi-targeted anti-cancer agents that generally interfere with DNA synthesis and inhibit topoisomerase II. But in addition, these tricyclic molecules often display secondary effects on other biochemical pathways including protein metabolism. In order to identify novel anti-cancer drugs, we evaluated the mechanism of action of a novel series of bis- and tetra-acridines. As expected, these molecules were found to interact with DNA and inhibit the topoisomerase II-mediated DNA decatenation. Interestingly when tested on human tumour cells either sensitive (HL-60) or resistant (HL-60/MX2) to topoisomerase II inhibitors, these molecules proved equicytotoxic against the two cell lines, suggesting that they do not only rely on topoisomerase II inhibition to exert their cytotoxic effects. In order to identify alternative targets, we tested the capacity of acridines 1-9 to inhibit the proteasome machinery. Four tetra-acridines inhibited the proteasome in vitro, with IC(50) values up to 40 times lower than that of the reference proteasome inhibitor lactacystin. Moreover, unlike peptide aldehydes used as reference inhibitors for the proteasome, these new acridine compounds demonstrated a good selectivity towards the proteasome, when tested against four unrelated proteases. A cellular assay based on the degradation of a proteasome protein substrate indicated that at least two of the tetra-acridines maintained this proteasome inhibition activity in a cellular context. This is the first report of tetra-acridines that demonstrate dual topoisomerase II and proteasome inhibition properties. This new dual activity could represent a novel anti-cancer approach to circumvent certain forms of tumour resistance.
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Centre de Recherche en Oncologie Expérimentale, Institut de Recherche Pierre Fabre, Parc Technologique du Canal, 3 rue des satellites, B.P. 94244, 31432 Toulouse Cedex 4, France. stephane.vispe@pierre-fabre.com
Vandenberghe
I
I
Robin
M
M
Annereau
J P
JP
Créancier
L
L
Pique
V
V
Galy
J P
JP
Kruczynski
A
A
Barret
J M
JM
Bailly
C
C
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D008954:Models, Biological; D015394:Molecular Structure; D046988:Proteasome Endopeptidase Complex / Q000032:analysis; D061988:Proteasome Inhibitors; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000166:Acridines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D061988:Proteasome Inhibitors; D059005:Topoisomerase II Inhibitors; D046988:Proteasome Endopeptidase Complex