Abstract
Vanadium compounds were studied during recent years to be considered as a representative of a new class of nonplatinum metal anticancer agents in combination to its low toxicity. Here, we found a vanadium compound Van-7 as an inhibitor of Topo I other than Topo II using topoisomerase-mediated supercoiled DNA relaxation assay. Agarose gel electrophoresis and comet assay showed that Van-7 treatment did not produce cleavable complexes like HCPT, thereby suggesting that Topo I inhibition occurred upstream of the relegation step. Further studies revealed that Van-7 inhibited Topo I DNA binding involved in its intercalating DNA. Van-7 did not affect the catalytic activity of DNase I even up to100 μM. Van-7 significantly suppressed the growth of cancer cell lines with IC50 at nanomolar concentrations and arrested cell cycle of A549 cells at G2/M phase. All these results indicate that Van-7 is a potential selective Topo I inhibitor with anticancer activities as a kind of Topo I suppressor, not Topo I poison.
Highlights
DNA topoisomerases which catalyze the interconversions of various topological states of DNA were originally discovered as activities that change the superhelical structure of closed circular DNAs [1]
Studies have shown that Topo I is associated with actively transcribed genes, whereas Topo II is required for DNA replication and for successful traverse of mitosis [2, 3]
Topo I is a molecular target of hydroxycamptothecine (HCPT) while Topo II is a molecular target of a number of clinically useful anticancer drugs such as etoposide (VP-16), doxorubicin, mitoxantrone and (N-[4-(9-acridinylamino)-3-methoxyphenyl] methanesulphonanilide) (m-AMSA)
Summary
DNA topoisomerases which catalyze the interconversions of various topological states of DNA were originally discovered as activities that change the superhelical structure of closed circular DNAs [1]. Based on their functional mechanisms, DNA topoisomerases have been classified into two types: type I DNA topoisomerases (Topo I) break and rejoin only one of the two strands during catalysis, while type II DNA topoisomerases (Topo II) break and rejoin both strands for each DNA strand-passing reaction. Other compounds such as saintopin, intoplicine, indoloquinolinedione derivatives, βlapachone, and related naphthoquinones have been shown to act on both Topo I and Topo II [6,7,8,9]
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