Visit our Expo - Redox and Inflammation signaling 2012

Session X : Cell death in cancer Poster X, 8
Bisnaphthalimidopropylspermidine induces DNA instability and apoptosis within colon
carcinoma derived cell lines
Charles S. Bestwick a, Lynda Ralton,c Lesley Milne,a Susan J. Duthie,b and Paul Kong
Thoo Linc
Molecular Nutrition Groupa and Nutrition and Epigenetics Groupb, The Rowett
Research Institute, Greenburn Road, Aberdeen AB29 9SB, Scotland, UK. The Robert
Gordon Universityc, School of Life Sciences, St. Andrew Street, Aberdeen AB25 1HG,
Scotland, UK. Email: C.Bestwick@rowett.ac.uk
DNA intercalators are potentially potent apoptosis inducers. Bisnaphthalimido compounds
bisintercalate to DNA via the major groove. However, solubility is poor and we have
modified the linker chain connecting the two naphthalimido ring moieties to increase
solubility. One such modification has been the incorporation of polyamines within the linker.
Polyamines are ubiquitous polycations critical for cell growth and also exhibit apoptotic
regulatory activity. Thus, in addition to facilitating cellular uptake, incorporating polyamines
within the linker may lead to an altered or extended spectrum of activity. Here, we describe
the effect of a spermidine analogue, bisnaphthalimidopropylspermidine (BNIPSpd), on DNA
stability and survival of Caco-2 and HT-29 colon carcinoma derived cells. After 48h
exposure, an IC50 of 0.15 and 1.64 micromolar was determined for Caco-2 and HT-29
respectively. Analogue uptake was rapid and essentially homogenous within the cell
populations by 4h. Uptake was associated with a dose dependent increase in DNA strand
breaks (0.1 –100micromolar) and decreased intracellular polyamines (0.01-100micromolar).
Following treatment with 0.5micromolar BNIPSpd or greater, cells expressed enhanced active
caspase-3, increased nuclear instability, internucleosomal DNA fragmentation and apoptoticmorphological
features. Pre-treatment with non-overtly cytotoxic or direct DNA damaging
concentrations of BNIPSpd retarded DNA repair capacity, as well as inducing a depletion of
cellular polyamines. The potential to exploit such analogues as chemotherapeutic agents and
as probes to assess the role of polyamines in cell survival regulation is discussed
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