microcystin and Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Bacterial Toxins; Cell Proliferation; Cyanobacteria; Cyanobacteria Toxins; Drug Delivery Systems; Drug Discovery; Marine Toxins; Microcystins; Neoplasms; Peptides

Topics: Animals; Antifungal Agents; Carcinogens; Ethers, Cyclic; Humans; Microcystins; Neoplasms; Okadaic Acid; Peptides, Cyclic; Phosphoprotein Phosphatases; Pyrans; Spiro Compounds; Structure-Activity Relationship

Microcystins (MCs) are the most prevalent cyanotoxins reported in freshwater. While numerous studies have examined the toxicological impacts of MCs on mammalian systems, very few have examined the chronic impacts of MCs on the gut microbiome of exposed organisms. Our understanding of the relationship of MCs, especially lysed toxic cyanobacteria, and the gut microbiota is very limited. The objective of this study was to determine the impacts of MC-LR and Microcystis lysate ingestion on the gut microbiome in a hepatocellular carcinoma mouse model, simulating a high-risk population and exposure at an environmentally relevant MC level. Mice were assigned to 4 groups (MC-LR; Microcystis lysate; Negative control; Positive (liver carcinogen) control). Fecal samples were collected every 8 weeks. Bacterial community and colony counts were analyzed. The abundance of Firmicutes in the positive control and lysate group was higher than the negative control and MC group. Exposure to MC-LR or lysate was associated with significantly decreased bacterial diversity. A distinct separation of the three groups (MC-LR/lysate/carcinogen) from the negative was much more apparent in their gut microbiome as the exposure time increased. The MC-LR and lysate groups showed gut microbiome structure responding to lipid metabolism disturbance and high stress. Bacterial colony count was significantly lower in all the treated groups than the negative control. Our study highlights that chronic exposure to MC-LR and Microcystis lysate negatively impacts gut microbiome succession and altered the bacterial community structure into the one similar to the carcinogen group, which may indicate that the change favors progression of hepatocellular carcinoma. In a future study, more in-depth investigation is warranted to better understand the liver-gut nexus in promoting liver cancer among those exposed to MC and toxic cyanobacteria.

Topics: Animals; Feces; Gastrointestinal Microbiome; Lipid Metabolism; Liver; Liver Neoplasms, Experimental; Mice; Mice, Inbred C3H; Microcystins; Microcystis; Neoplasms; Toxins, Biological

Microcystins are potent phosphatase inhibitors and cellular toxins. They require active transport by OATP1B1 and OATP1B3 transporters for uptake into human cells, and the high expression of these transporters in the liver accounts for their selective hepatic toxicity. Several human tumors have been shown to have high levels of expression of OATP1B3 but not OATP1B1, the main transporter in liver cells. We hypothesized that microcystin variants could be isolated that are transported preferentially by OATP1B3 relative to OATP1B1 to advance as anticancer agents with clinically tolerable hepatic toxicity. Microcystin variants have been isolated and tested for cytotoxicity in cancer cells stably transfected with OATP1B1 and OATP1B3 transporters. Microcystin variants with cytotoxic OATP1B1/OATP1B3 IC50 ratios that ranged between 0.2 and 32 were found, representing a 150-fold range in transporter selectivity. As microcystin structure has a significant impact on transporter selectivity, it is potentially possible to develop analogs with even more pronounced OATP1B3 selectivity and thus enable their development as anticancer drugs.

Topics: Cell Line, Tumor; Humans; Inhibitory Concentration 50; Liver-Specific Organic Anion Transporter 1; Microcystins; Neoplasms; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Peptides, Cyclic; Solute Carrier Organic Anion Transporter Family Member 1B3