Quinolones as enhancers of camptothecin-induced cytotoxic and anti-topoisomerase I effects

Abstract

Camptothecins (CPTs) are topoisomerase I (topo I) inhibitor chemotherapeutic agents. Studies indicate that combination therapy is needed in most therapeutic protocols with camptothecins. Certain fluoroquionolones inhibit topoisomerase II activity in eukaryotic cells. We showed previously that the fluoroquionolone moxifloxacin inhibited purified human topoisomerase II, acted synergistically with etoposide and enhanced anti-proliferative effect in THP-1 and Jurkat cells. There is no information on flouroquionolone's activity on topoisomerase I. We examined the effect of moxifloxacin and ciprofloxacin alone or in combination with camptothecin on purified topoisomerase I activity and further analysed their combined activity on proliferation and apoptosis in HT-29 cells. Moxifloxacin and ciprofloxacin alone slightly inhibited purified topoisomerase I activity; however in combination with camptothecin it led to a 82% and 64% reduction in enzyme activity, respectively. Moreovwer, our studies indicate that incubation of HT-29 cells with a combination of moxifloxacin or ciprofloxacin with CPT increases cellular topoisomerase I inhibitory activity. In cell proliferation assays, addition of moxifloxacin to 1nM camptothecin enhanced its cytotoxic activity by three-fold and was similar to that of 50nM camptothecin alone (45+/-2.1% inhibition). Ciprofloxacin enhanced cytotoxic activity to a lesser extent. Apoptosis studies showed up to 1.6-fold increase in annexin V positive cells when the fluoroquinolones were combined with camptothecin as compared to camptothecin alone. Analysis of the proangiogenic factors IL-8 and VEGF showed significant reduction in IL-8 production by moxifloxacin and ciprofloxacin up to 48% and in VEGF secretion from the cells. Further in vivo and clinical studies of camptothecins combined with the above fluoroquinolones are warranted.