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.