Cyanobacterial Cyclopeptides as Lead Compounds to Novel Targeted Cancer Drugs

Abstract

Cyanobacterial cyclopeptides, including microcystins and nodularins, are considered a health hazard to humans due to the possible toxic effects of high consumption. From a pharmacological standpoint, microcystins are stable hydrophilic cyclic heptapeptides with a potential to cause cellular damage following uptake via organic anion-transporting polypeptides (OATP). Their intracellular biological effects involve inhibition of catalytic subunits of protein phosphatase 1 (PP1) and PP2, glutathione depletion and generation of reactive oxygen species (ROS). Interestingly, certain OATPs are prominently expressed in cancers as compared to normal tissues, qualifying MC as potential candidates for cancer drug development. In the era of targeted cancer therapy, cyanotoxins comprise a rich source of natural cytotoxic compounds with a potential to target cancers expressing specific uptake transporters. Moreover, their structure offers opportunities for combinatorial engineering to enhance the therapeutic index and resolve organ-specific toxicity issues. In this article, we revisit cyanobacterial cyclopeptides as potential novel targets for anticancer drugs by summarizing existing biomedical evidence, presenting structure-activity data and discussing developmental perspectives.

Baltic cyanobacteria – a source of biologically active compounds

“…Due to the inhibitory effect on PP, the acute toxins, microcystins and nodularins, are also considered to be potential anticancer drug candidates (Monks et al, 2007;Sainis et al, 2010). In mammalian organisms exposed to microcystins, the toxins cross cell membranes of hepatocytes through the organic anion-transporting polypeptides (OATP).…”

“…As a consequence, the cancer cells are more sensitive to MCs and experience cytotoxic effects at lower concentrations than normal cells. Work on MC variants with high selectivity against cancer-specific OATPs is in progress (Monks et al, 2007;Sainis et al, 2010).…”

Current Approaches for Enhanced Expression of Secondary Metabolites as Bioactive Compounds in Plants for Agronomic and Human Health Purposes

“…The secondary metabolites produced in cyanobacteria play an important role in toxicity as iron chelators, protease inhibitors, growth inhibitors as well as growth promoting properties and have been well documented [Prasanna et al, 2010;Yadav et al, 2011]. Some metabolites such as microcystins, saxitoxins or anatoxins, are of global signifi cance because of their toxicity while other display signifi cant pharmaceutical potential [Sainis et al, 2010]. It has been found that the cyanotoxins, anatoxin-a, microcystins and cylindrospermopsin obtained from Anabaena, Microcystis and Cylindrospermopsis (respectively), show larvicidal activity with >50% mortality.…”

Anticancer compounds from cyanobacterium Lyngbya species: a review

“…Since, there is a commonality of the control of cancer types broadly by the inhibition of a target protein, responsible for the origin of cancer stem cells (Costa et al 2012;Dixit and Suseela 2013), it can be envisaged that the concept of the development of ADCs, in a systematic approach, could be widely adopted with the involvement of a natural compound. The development of emulative and efficacious drugs for the diverse cancer types, individually as well as holistically, is still an elusive goal in pharmaceutics, today; and bioactive compounds of Lyngbya are used to target cancer macromolecules, tubulin or actin filaments, protein kinase, microtubule, calcium influx, serine proteases, caspase, Bcl-2 protein, voltage-gated sodium channel and cancer related secretary pathways inhibition in eukaryotic cells (Márquez et al 1998;Newman and Cragg 2004;Perez et al 2005;Simmons et al 2005;Watanabe et al 2006;Tabuchi et al 2009;Oftedal et al 2010;Sainis et al 2010).…”