From Antarctica to cancer research: a novel human DNA topoisomerase 1B inhibitor from Antarctic sponge Dendrilla antarctica

Abstract

Nature has been always a great source of possible lead compounds to develop new drugs against several diseases. Here we report the identification of a natural compound, membranoid G, derived from the Antarctic sponge Dendrilla antarctica displaying an in vitro inhibitory activity against human DNA topoisomerase 1B. The experiments indicate that membranoid G, when pre-incubated with the enzyme, strongly and irreversibly inhibits the relaxation of supercoiled DNA. This compound completely inhibits the cleavage step of the enzyme catalytic mechanism by preventing protein binding to the DNA. Membranoid G displays also a cytotoxic effect on tumour cell lines, suggesting its use as a possible lead compound to develop new anticancer drugs.

Dimethylmyricacene: An In Vitro and In Silico Study of a Semisynthetic Non-Camptothecin Derivative Compound, Targeting Human DNA Topoisomerase 1B

“…To characterize which step of the hTop1 catalytic mechanism is affected by DM, the enzyme activity was evaluated on a suicide substrate (SS) in the absence and presence of DM, in a time course experiment, as in [ 30 ]. Briefly, the experiment was performed with a fluorescently labelled SS made by the CL14-FITC annealed to the CP25-P oligonucleotide phosphorylated at the 5′ end, to produce a duplex with a 5′ single-strand overhang ( Figure 3 A).…”

“…To analyze the cleavage kinetics, the CL14-FITC oligonucleotide was annealed to a CP25-P complementary strand to assemble both cleavage and religation substrates, hereafter indicated as suicide substrate (SS). The cleavage reaction was performed at different time points with 100 μM of DM, by incubating 0.6 pmol of SS with 1.2 pmol hTop1 (Prospec), as previously described [ 30 ]. The reactions were stopped by adding 0.5% SDS.…”

Marine natural products

“…473 In other reports, the mode of anti-colorectal cancer action of merosesquiterpenoid ilimaquinone is via mitochondrial-mediated apoptosis, caused by activation of caspase-9/-3 and the subsequent DNA damage caused, 474 while spongian diterpenoid membranolide G irreversibly inhibits relaxation of supercoiled DNA via inhibition of topoisomerase 1B and it may therefore be a new anti-cancer lead compound. 475 The biosynthesis of macrolide lasonolide A ( Forcepia sp.) has been accomplished using a metagenomic approach, suggesting the potent (nM) cytotoxin is made by the first member of new bacterial genus Candidatus Thermopylae lasonolidus, whose nearest taxonomic neighbour is Pedosphaera parvula .…”

A Chemo-Ecological Investigation of Dendrilla antarctica Topsent, 1905: Identification of Deceptionin and the Effects of Heat Stress and Predation Pressure on Its Terpene Profiles

“…Similarly, changes in predation pressures may also produce changes in these natural products [ 31 ]. Some of the sponge compounds can display relevant bioactivities in the laboratory too [ 19 , 24 , 25 , 32 , 33 , 34 ]. D. antarctica compounds have been described as having antibacterial, antifungal, or cytotoxic activity, among others.…”