Antitumoral and mechanistic studies of ianthelline isolated from the Arctic sponge Stryphnus fortis.
BACKGROUND
Ianthelline was isolated from the Arctic sponge Stryphnus fortis. The structure of the compound has been previously described. However, only limited bioactivity data are available and little has been reported about the cytotoxic potential of ianthelline since its discovery. In addition, no study has so far aimed at identifying which cellular mechanisms are affected by ianthelline to generate cytotoxicity.


METHODS
The cytotoxicity of ianthelline was tested against one non-malignant and ten malignant cell lines. The effects of ianthelline on key cell division events were studied in sea urchin embryos. Tyrosine kinase ABL (ABL), cAMP-dependent protein kinase A (PKA), protein-tyrosine phosphatase 1B (PTP1B), and a panel of 131 kinases were further tested for sensitivity to ianthelline.


RESULTS
Ianthelline inhibits cellular growth in a dose- and time-dependent manner. Disturbed mitotic spindle formation was found in sea urchin embryos exposed to ianthelline. In addition, pronuclear migration and cytokinesis were severely inhibited. No effect on DNA synthesis was detectable. Ianthelline did not significantly inhibit ABL, but did provoke weak dose-dependent inhibition of PKA and PTP1B. It strongly inhibited the activity of 1 out of 131 tested kinases (to residual activity <10 %), with a Gini co-efficient of 0.22 for the degree of selectivity of kinase inhibition.


CONCLUSIONS
These results demonstrate that ianthelline is a cytotoxic marine compound, which exerts its antiproliferative effects by several mechanisms that include inhibition of mitotic spindle formation and inhibition of protein kinase activity.
Centre for Research-based Innovation on Marine Bioactivities and Drug Discovery, MabCent, University of Tromsø, Breivika, Tromsø, Norway. kine.o.hanssen@uit.no
Kine Ø
KØ
Hanssen
Jeanette H
JH
Andersen
Trine
T
Stiberg
Richard A
RA
Engh
Johan
J
Svenson
Anne-Marie
AM
Genevière
Espen
E
Hansen
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy; D008545:Melanoma / Q000188:drug therapy; D011161:Porifera / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012617:Sea Urchins / Q000187:drug effects / Q000196:embryology; D008941:Spindle Apparatus / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D001688:Biological Products; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; C577283:ianthelline; D014443:Tyrosine