Dinoflagellates and Toxin Production 221
cultures of Gambierdiscus toxicus (Bomber et al. 1989) and Prorocentrum convaum (Carlson et al. 1984).
It is known that dinoflagellates (at least some species) have the ability to engulf other cells by a cascade
of endosymbiotic events, and associate bacteria to their nucleus or cytoplasm. In addition, presence of
bacteria in the medium may affect toxicity of cultures. For instance, Gyrodinium instriatum was found
to be toxic when co-cultured with Pseudomonas sp., previously collected from a culture of Alexandrium
tamarensis (Silva 1990). It was suggested that a close relationship between dinoflagellates and bacteria
may induce toxicogenesis; this may also explain why non-toxic dinoflagellates were developed toxicity
under certain conditions (Steidinger and Baden 1984). However, it should be stressed that not all toxic
species possess intracellular bacteria, yet further studies are still warranted; for instance, several studies
on Karenia brevis were unable to show any bacterial profiles (Steidinger and Baden 1984).
Dinoflagellate toxin applications
Although dinoflagellates are associated to HABs, their ability to synthesize some of the largest and most
complex polyketides (and other secondary metabolites) discovered to date (Rein and Borrone 1999;
Kellmann et al. 2010) make them a valuable natural source of marine biotoxins. With a wide spectrum
of chemical structures, and an even wider number of biological activities to different levels of potency,
they have found (or will likely find) potential applications in human and veterinary medicine (GallardoRodríguez et al. 2012a). Examples include saxitoxin and tetrodotoxin—produced by dinoflagellates
causing PSP, useful as topical anesthetics (Kohane et al. 2000; Duncan et al. 2001) and pain management
(Nieto et al. 2012). In fact a powerful drug from the potent neurotoxin tetrodotoxin is currently being
developed in Canada by Wex Pharmaceuticals, and undergoing Phase III clinical trials with great success
as pain controller in cancer patients (Berde et al. 2011). However, tetrodotoxin used to produce this drug
has been sourced from pufferfish—since the production by dinoflagellates has not yet attained sufficiently
high levels (Gallardo-Rodríguez et al. 2012a). Okadaic acid, known to be associated with DSP species,
is a neurotoxin used as model to study the therapeutical effects in some neurodegenerative disorders
(e.g., Alzheimer’s, or memory-impairment) (Kamat et al. 2013); yessotoxin, isolated from DSP-causing
agents, as appears to be a potential bioactive agent against melanoma cancer (in vivo and in vitro), to
possess anti-fungal activity and possibly having a role in immune regulation (asthma treatment) (Tobío
et al. 2016); gonyautoxin, produced by dinoflagellate Amphydinium spp., is now safely used as part of
a therapeutical approach against acute or chronic anal fissures (Garrido et al. 2005); neosaxitoxin as a
topical formulation to prolonged anesthesia from PSP dinoflagellates (Rodriguez-Navarro et al. 2007);
amphidinolides and colopsinols, derived from Amphidium genus, are reported as potential antitumoral
agents against lymphoma and epidermic carcinoma (Kobayashi and Tsuda 2004); gymnocin-A, a
complex polyether toxin isolated from the red tide dinoflagellate Gymnodinium mikimotoi, has revealed
to be cytotoxic against P388 mouse leukemia cells (Tsukano and Sasaki 2006); goniodomin-A, reported
in dinoflagellates causing PSP, is considered as effective antifungal and antiangiogenic agent (Abe et
al. 2002); pectenotoxins, derived from dinoflagellates causing DSP, can act as chemotherapeutic agents
against p53-defficient tumors (Chae et al. 2005); ostreocins and palytoxins, isolated from the Ostreopsis
genus, include several pharmacological actions, such as modulation of a few neurotransmitters (e.g.,
norepinephrine and/or acetylcholine) and activation of pro-inflammatory signaling cascades (Pelin et al.
2016); symbiospirols (symbioimine and neosymbioimine), obtained from cultivated symbiotic marine
dinoflagellate Symbiodinium sp., have been claimed to be antiosteoporosis agents (Kita et al. 2005);
karlotoxins, produced by species Karlodinium veneficum, has apparently a hypocholestermic role and
an anti-tumoral role (Waters et al. 2011); gambieric acid and gambierol, both unequivocally isolated
from species Gambierdiscus toxicus, revealed potential as anti-filamentous fungal agent and modulator
of Alzheimer’s disease, respectively (Nagai et al. 1993); and brevetoxins and their derivatives, mainly
reported in Karenia brevis as major contributor of NSP, are regulators of immune system and pulmonary
diseases (i.e., cystic fibrosis) (Abraham et al. 2005).
cultures of Gambierdiscus toxicus (Bomber et al. 1989) and Prorocentrum convaum (Carlson et al. 1984).
It is known that dinoflagellates (at least some species) have the ability to engulf other cells by a cascade
of endosymbiotic events, and associate bacteria to their nucleus or cytoplasm. In addition, presence of
bacteria in the medium may affect toxicity of cultures. For instance, Gyrodinium instriatum was found
to be toxic when co-cultured with Pseudomonas sp., previously collected from a culture of Alexandrium
tamarensis (Silva 1990). It was suggested that a close relationship between dinoflagellates and bacteria
may induce toxicogenesis; this may also explain why non-toxic dinoflagellates were developed toxicity
under certain conditions (Steidinger and Baden 1984). However, it should be stressed that not all toxic
species possess intracellular bacteria, yet further studies are still warranted; for instance, several studies
on Karenia brevis were unable to show any bacterial profiles (Steidinger and Baden 1984).
Dinoflagellate toxin applications
Although dinoflagellates are associated to HABs, their ability to synthesize some of the largest and most
complex polyketides (and other secondary metabolites) discovered to date (Rein and Borrone 1999;
Kellmann et al. 2010) make them a valuable natural source of marine biotoxins. With a wide spectrum
of chemical structures, and an even wider number of biological activities to different levels of potency,
they have found (or will likely find) potential applications in human and veterinary medicine (GallardoRodríguez et al. 2012a). Examples include saxitoxin and tetrodotoxin—produced by dinoflagellates
causing PSP, useful as topical anesthetics (Kohane et al. 2000; Duncan et al. 2001) and pain management
(Nieto et al. 2012). In fact a powerful drug from the potent neurotoxin tetrodotoxin is currently being
developed in Canada by Wex Pharmaceuticals, and undergoing Phase III clinical trials with great success
as pain controller in cancer patients (Berde et al. 2011). However, tetrodotoxin used to produce this drug
has been sourced from pufferfish—since the production by dinoflagellates has not yet attained sufficiently
high levels (Gallardo-Rodríguez et al. 2012a). Okadaic acid, known to be associated with DSP species,
is a neurotoxin used as model to study the therapeutical effects in some neurodegenerative disorders
(e.g., Alzheimer’s, or memory-impairment) (Kamat et al. 2013); yessotoxin, isolated from DSP-causing
agents, as appears to be a potential bioactive agent against melanoma cancer (in vivo and in vitro), to
possess anti-fungal activity and possibly having a role in immune regulation (asthma treatment) (Tobío
et al. 2016); gonyautoxin, produced by dinoflagellate Amphydinium spp., is now safely used as part of
a therapeutical approach against acute or chronic anal fissures (Garrido et al. 2005); neosaxitoxin as a
topical formulation to prolonged anesthesia from PSP dinoflagellates (Rodriguez-Navarro et al. 2007);
amphidinolides and colopsinols, derived from Amphidium genus, are reported as potential antitumoral
agents against lymphoma and epidermic carcinoma (Kobayashi and Tsuda 2004); gymnocin-A, a
complex polyether toxin isolated from the red tide dinoflagellate Gymnodinium mikimotoi, has revealed
to be cytotoxic against P388 mouse leukemia cells (Tsukano and Sasaki 2006); goniodomin-A, reported
in dinoflagellates causing PSP, is considered as effective antifungal and antiangiogenic agent (Abe et
al. 2002); pectenotoxins, derived from dinoflagellates causing DSP, can act as chemotherapeutic agents
against p53-defficient tumors (Chae et al. 2005); ostreocins and palytoxins, isolated from the Ostreopsis
genus, include several pharmacological actions, such as modulation of a few neurotransmitters (e.g.,
norepinephrine and/or acetylcholine) and activation of pro-inflammatory signaling cascades (Pelin et al.
2016); symbiospirols (symbioimine and neosymbioimine), obtained from cultivated symbiotic marine
dinoflagellate Symbiodinium sp., have been claimed to be antiosteoporosis agents (Kita et al. 2005);
karlotoxins, produced by species Karlodinium veneficum, has apparently a hypocholestermic role and
an anti-tumoral role (Waters et al. 2011); gambieric acid and gambierol, both unequivocally isolated
from species Gambierdiscus toxicus, revealed potential as anti-filamentous fungal agent and modulator
of Alzheimer’s disease, respectively (Nagai et al. 1993); and brevetoxins and their derivatives, mainly
reported in Karenia brevis as major contributor of NSP, are regulators of immune system and pulmonary
diseases (i.e., cystic fibrosis) (Abraham et al. 2005).