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Review
. 2010 Mar 15;8(3):629-57.
doi: 10.3390/md8030629.

Cyanobacterial cyclopeptides as lead compounds to novel targeted cancer drugs

Ioannis Sainis  1 , Demosthenes Fokas, Katerina Vareli, Andreas G Tzakos, Valentinos Kounnis, Evangelos Briasoulis
Affiliations
Review

Cyanobacterial cyclopeptides as lead compounds to novel targeted cancer drugs

Ioannis Sainis et al. Mar 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.

Keywords: OATP; cancer; cyanobacteria; cyanotoxins; membrane transporters; microcystin; targeted-therapy.

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Figures

Figure 1
Figure 1
Typical colony-forming cyanobacteria found in a toxic bloom in a Mediterranean lake (Lake Pamvotis Greece). A. Anabaena sp. B. Microcystis sp.
Figure 2
Figure 2
Structures of the most common isolated MCs and nodularins.
Figure 3
Figure 3
Cancer cell molecular targets and actions of cyanobacterial cyclopeptides. (MC = microcystin, NOD = nodularin, OATP = Organic Anion Transporting Polypeptides, PP = protein phosphatase, MPT = Mitochondrial permeability transition, ROS = reactive oxygen species, GSH = glutathione, CYP2E1 = Cytochrome P450 2E1, red cross symbol = inhibition, green cross symbol = consumption, black lines symbolize established action, grey lines symbolize likely actions).
Figure 4
Figure 4
Conjugate addition of a wide range of nucleophiles to MC-LR.
Figure 5
Figure 5
A combinatorial approach to structurally diverse microcystins.
See this image and copyright information in PMC

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