The dynamin inhibitors MiTMAB and OcTMAB induce cytokinesis failure and inhibit cell proliferation in human cancer cells.
The endocytic protein dynamin II (dynII) participates in cell cycle progression and has roles in centrosome cohesion and cytokinesis. We have described a series of small-molecule inhibitors of dynamin [myristyl trimethyl ammonium bromides (MiTMAB)] that competitively interfere with the ability of dynamin to bind phospholipids and prevent receptor-mediated endocytosis. We now report that dynII functions specifically during the abscission phase of cytokinesis and that MiTMABs exclusively block this step in the cell cycle. Cells treated with MiTMABs (MiTMAB and octadecyltrimethyl ammonium bromide) and dyn-depleted cells remain connected via an intracellular bridge for a prolonged period with an intact midbody ring before membrane regression and binucleate formation. MiTMABs are the first compounds reported to exclusively block cytokinesis without affecting progression through any other stage of the cell cycle. Thus, MiTMABs represent a new class of antimitotic compounds. We show that MiTMABs are potent inhibitors of cancer cell growth and have minimal effect on nontumorigenic fibroblast cells. Thus, MiTMABs have toxicity and antiproliferative properties that preferentially target cancer cells. This suggests that dynII may be a novel target for pharmacologic intervention for the treatment of cancer.
Joshi
Sanket
S
Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales, Australia.
Perera
Swetha
S
Gilbert
Jayne
J
Smith
Charlotte M
CM
Mariana
Anna
A
Gordon
Christopher P
CP
Sakoff
Jennette A
JA
McCluskey
Adam
A
Robinson
Phillip J
PJ
Braithwaite
Antony W
AW
Chircop
Megan
M
D000473:Alkanes / Q000494:pharmacology*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D048749:Cytokinesis / Q000187:drug effects*; D003902:Detergents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D034622:RNA Interference; D050337:Trimethyl Ammonium Compounds / Q000494:pharmacology*
D000473:Alkanes; D003902:Detergents; D000644:Quaternary Ammonium Compounds; D050337:Trimethyl Ammonium Compounds; C518260:octadecyltrimethylammonium bromide; D020558:GTP Phosphohydrolases; D034281:Dynamins; C009410:tetradecyltrimethylammonium