Cyanobacterial Toxin Cylindrospermopsin: It’s Possible Pathway from Poisoning to Cancer Curing

    

    

    Figure 2:  Structures of the most common isolatedCylindrospermopsin. IUPAC
(International Union of Pure and Applied Chemistry ) name; 2,4(1H,3H)-
Pyrimidinedione, 6-[(R)-hydroxy[(2aS,3R,4S,5aS,7R) -2,2a,3,4,5,5a,6,7-
octahydro-3-methyl-4-(sulfooxy) -1H-1,8,8b-triazaacenaphthylen-7-yl]
methyl]-.
    
    

Almost CYN complete structure was illustrated by Ohtani et al. [19] using Mass Spectroscopy (MS) and Nuclear Magnetic Resonance (NMR). However, later, it was found a false feature in the first identification as the orientation of the hydroxyl group, that was adjacent to uracil ring, it was corrected from epimerto 7-epicylindrospermopsin by Banker et al. [20]. This toxin was identified as a minor metabolite from A.ovalisporum that was isolated first from Lake Kinneret in Israel. In addition, Norris et al. in 1999 were able to isolate CYN (a toxic minor metabolite of A. ovalisporum) by Solid Phase Extraction (SPE) followed by semipreparative chromatography.

Toxicology

The only human toxicity associated cases with CYN were reported at the Palm Island hepato enteritis in 1979, where 148 people were hospitalized. The epidemiological investigation was summarized by Bourke et al. [18] revealed that people affected were mainly children they which had drunk CYA contaminated water that were supplied by reticulated system. The epidemic that consisted of three clear stages: a hepatitis phase (lasted 2 days), a lethargic phase (lasted 1-2 days) and a diarrhoeal phase (5 days of duration). While; the first report of the toxic effects of CYN in mouse model was noticed by Hawkins et al. [21] who used an extract of the original Palm Island strain in his experiment. Hawkins indicated that; the poisoned mice displayed anorexia, diarrhoea and gasping respiration. The autopsy data showed haemorrhages in the lungs, livers, kidneys, small intestines and adrenal glands. While, the Histopathological data showed a dose dependent necrosis in the hepatocytes, lipid accumulation and fibrinthrombi formation in blood vessels of the liver and lungs, along with varying epithelial cell necrosis in areas of the kidneys. Consequently and after identifying the chemical structure of CYN, Ohtani et al. [19] reported the LD50 of the pure CYN after i.p. administration in mice, he indicated that’ CYN had LC50 of 2.1mg/kg over 24 h and 0.2mg/kg lasting 5–6 days. Recently, Reid et al. [22] used Embryonic Stem Cell (mES) to evaluate the in vitro embryo-toxicity of CYN. They clarified that, after 24 hr, mES cells could tolerate toxins concentration up to 0.5 μg/mL without any morphological changes and the recorded toxin IC50 reached CYN 0.86 μg/mL. Another study was done by Humpage, et al. [23], the authors tested the effect of the purified cylindrospermopsin by daily gavage to male Swiss albino mice with doses 0, 30, 60, 120, or 240 μg/kg-day (10 mice per dose group) for 11 weeks. No deaths were reported in the study and they explained that, the kidney was the most sensitive organ to the toxin that increased in weigh in a dose-dependent manner starting at 60 μg/kg-day. Starting with the previous reports that support the finding; CYN was not toxic at concentrations up to 10 μg /L [24], we could mention that Low concentrations of cylindrospermopsin could be a promising therapeutic anticancer agent.

The Possibility of usage the Cyanobacterial Cylindrospermopsin toxins as Anticancer Agent

In cancer patients, the tumor cells that could survive during the chemotherapy often emerge with increased resistant to the treated drug in phenomenon could Multidrug Resistant (MDR). Different genera of Cyanobacteria as Anabaena, Oscillatoria and Microcystis considered as rich source of cytotoxic compounds that have a potential effect to target specific active uptake transporters in MDR cancer cells [24]. Theses toxins could be found in form of acyclic peptides, linear decadepsipeptides, lipophylic cyclic peptides and macrolactones that are very toxic to various cancer cell lines [24], these toxins could be potent 100-1000 times than the available anticancer drugs [25].

Marine cyanobacterial toxic metabolites as cylindrospermopsin exhibit important biological features by interfering in signal transduction either through sodium channels activation or by targeting signaling apoptosis proteins (Figure 3). The pharmacological importance of these toxins were not explained well up till now while; few reports explained that its important resides in their abilities to alter the cellular proliferation and growth rates of cancer cell lines [26]. The possible role of the tumor suppressor protein p53 in cylindrospermopsin-induced gene expression in human hepatocellular carcinoma cell line HepG2 was examined by Bain et al. [27]. The author clarified that After 24 hr, in HepG2 treated cells with cylindrospermopsin, there are an early concentration-dependent increases in mRNA levels of the p53 target genes CDKN1A, GADD45alpha, BAX and MDM2.

    

    

    Figure 3:  The molecular mechanisms of Cylindrospermopsin (CYN) toxicity
through the inhibition of Glutathione (GSH) and protein synthesis, as well as
Cytochrome P450 (CYP450), and CYN interaction with DNA. Valério et
al. [30].