Cephalochordata

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Phylum Chordata
Cephalochordata (lancelets)
Urochordata (tunicates)
Agnatha (jawless fish, e.g. lampreys)
Placodermi (jawfish) -EXTINCT
Chondrichthyes (sharks and rays)
Osteichthyes (bony fish)
Amphibia
Vertebrates
Reptilia
Aves (birds)
Mammalia
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Phylum Chordata
Cephalochordata (lancelets)
Urochordata (tunicates)
Agnatha (jawless fish, e.g. lampreys)
Placodermi (jawfish) -EXTINCT
Chondrichthyes (sharks and rays)
Osteichthyes (bony fish)
Amphibia
Vertebrates
Reptilia
Aves (birds)
Mammalia
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Marine Mammals
4
Marine Fish
Class Chondrichthyes (cartilaginous fish)
Class Osteichthyes (bony fish)
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Bioactive Compounds from Osteichthyes Tetrodotoxi
n
Fugu spp. (Pufferfish) and others.
Tetrodotoxin (TTX)
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Voltage-Gated Sodium Channels

- - - - - - - -
Voltage-Gated Ion Channels
K
Na
7
Action Potential
Action Potential
50
Depolarizing Phase
0
Repolarizing Phase
Membrane Potential (mV)
- 50
Threshold
Resting Potential
- 70
Time (milliseconds)
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Voltage-Gated Sodium Channels

- - - -- - - - -
Action Potential
K
Na
9
TTX Inhibits Depolarization (Action Potential) in
Neurons
TTX
Cell-Specific
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TTX Binds and Blocks Voltage-Gated Sodium Channels
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Bioactive Compounds from Chondrichthyes
Other Myths/Misconceptions? Sharks Dont Have
Immune Systems, But Dont Get Infections
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Dietary Supplements from Sharks
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Shark Oil or Snake Oil?
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Shark Liver Oil
Ingredients 71.9 Petrolatum 14 Mineral Oil 3
Shark Liver Oil 0.25 Phenylephrine HCl
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Bioactive Compounds from Chondrichthyes
Squalamine
Stomach Tissue (400 g)
Squalus acanthias (Dogfish Shark)
Extract 60 CH3CN/1 TFA
Extract Lipids Folch Method 21 CHCl3/MeOH,
Salt Wash
Aqueous Phase
Gel Filtration (Bio-Gel P-30)
C18 HPLC
SCX HPLC (Ion Exchange)
C4 HPLC
FAB-MS, 1H- and 13C-NMR, 2-D NMR (NOESY, HMQC)
Moore et al. (1993) Proc. Natl. Acad. Sci., 90
1354-8.
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Squalamine MW 628.4739
Moore et al. (1993) Proc. Natl. Acad. Sci., 90
1354-8.
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Condensation of Squalene and Spermidine
Spermidine
Squalene
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Tissue Distribution of Squalamine
Amount Tissue (µg/g tissue) Stomach 1 L
iver 4-7 Gallbladder 4-7 Spleen 2 Testes
2 Gills 0.5 Intestine 0.02
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Squalamine Inhibits Na/H Exchanger (NHEs)
Brush Border Cells
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Squalamine Inhibits Na/H Exchanger (NHEs)
PS120 Fibroblasts (No NHE)
Akhter et al. (1999) Am. J. Physiol., 276 136-44.
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Squalamine Inhibits H Efflux in NHE3-Transformed
Cells
Akhter et al. (1999) Am. J. Physiol., 276 136-44.
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Squalamine Inhibition is Dose-Dependent
Akhter et al. (1999) Am. J. Physiol., 276 136-44.
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Squalamine Does NOT Inhibit H Efflux in NHE1- or
NHE2-Transformed Cells
Akhter et al. (1999) Am. J. Physiol., 276 136-44.
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Squalamine Inhibition of NHE3-Transformed Cells
Requires COOH Terminal (76 Amino Acids)
Akhter et al. (1999) Am. J. Physiol., 276 136-44.
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Squalamine Inhibits Na/H Exchange in Rabbit
Illeal Brush Border Vesicles
22Na Uptake
Akhter et al. (1999) Am. J. Physiol., 276 136-44.
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Squalamine Inhibits Tumor Angiogenesis
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Tumors Recruit Vascular Endothelial Cells in
Angiogenesis
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Vascular Endothelial Growth Factor (VEGF)
Stimulates Vessel Formation
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VEGF Acts Via Mitogen-Associated Protein Kinase
(MAPK)
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MAPK Phosphorylation is pH Dependent
Stathopoulou et al. (2006) J. Exp. Biol., 209
1344-54.
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Squalamine Inhibits VEGF-Induced Phosphorylation
of MAPK
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Squalamine Inhibition of NHE3-Transformed Cells
Requires COOH Terminal (76 Amino Acids)
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Pre-Clinical Trials with Squalamine
Xenograft Mice Lung, Breast, Ovarian and
Prostate Cancer Allograft Rats Brain and Breast
Cancer Inhibit Tumor Growth and Angiogenesis
Phase I/IIa Clinical Trials with Squalamine
Lung and Ovarian Cancer MTD 384 mg/m2/day
120-h Continuous Infusion Co-Administration with
Other Drugs
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Co-Administration of Squalamine
Control
Cisplatin Squalamine
Cisplatin Squalamine
Schiller and Bittner (1999) Clin. Cancer Res., 5
4287-94
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Squalamine and Macular Degeneration
Squalamine Lactate (MSI-1256F) EVIZON (Genaera
Pharmaceuticals)
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