Some polyamine derivatives, namely the bisnaphthalimidopropyl polyamines (BNIPPs) may have potential as anticancer
drugs. Indeed, previous work from some of us had shown that the ability of these molecules to bind to DNA may contribute to their
cytotoxicity. However, their precise mode of action has not been fully understood.
In the present work, we report for the first time the effect of the previously synthesised compounds, BNIPDaCHM and NPA, together
with a new BNIP derivative (BNIP-3,4-DaDPM) in the in vitro growth of a non-small cell lung cancer cell line (NCI-H460). In addition,
for the most potent compound (BNIPDaCHM), its activity as sirtuin inhibitor was investigated in vitro and further confirmed in silico.
Results in the NCI-H460 cells showed that, from the compounds tested, BNIPDaCHM was the most potent (GI50 of 1.3 μM). In addition,
a concentration-dependent alteration in the normal NCI-H460 cell cycle profile was observed following treatment with BNIPDaCHM as
well as an increase in the sub-G1 peak (suggestive of apoptotis). This effect was further supported by Annexin V/PI staining and by
analysing the expression of proteins related to apoptosis (cleaved PARP and Caspase-3) by Western blot. It was also observed that
BNIPDaCHM inhibited the activity of SIRT2 in vitro, but not of SIRT1. Accordingly, this compound also caused a small increase in
tubulin acetylation in NCI-H460 cells. To determine the binding potential of BNIPDaCHM on hSIRT2 and to further validate its
inhibitory action, in silico docking studies were carried out, which revealed that BNIPDaCHM is composed of an entirely new SIRT2-
inhibiting structural scaffold. In conclusion, this study indicates that BNIP derivatives with a novel structural backbone, such as
BNIPDaCHM, may have potential as building blocks for novel antitumour agents which might selectively bind to hSIRT-2.