Document Detail

Mitochondrial genome-knockout cells demonstrate a dual mechanism of action for the electron transport complex I inhibitor mycothiazole.
MedLine Citation:
PMID:  22690150     Owner:  NLM     Status:  MEDLINE    
Mycothiazole, a polyketide metabolite isolated from the marine sponge Cacospongia mycofijiensis, is a potent inhibitor of metabolic activity and mitochondrial electron transport chain complex I in sensitive cells, but other cells are relatively insensitive to the drug. Sensitive cell lines (IC(50) 0.36-13.8 nM) include HeLa, P815, RAW 264.7, MDCK, HeLa S3, 143B, 4T1, B16, and CD4/CD8 T cells. Insensitive cell lines (IC(50) 12.2-26.5 μM) include HL-60, LN18, and Jurkat. Thus, there is a 34,000-fold difference in sensitivity between HeLa and HL-60 cells. Some sensitive cell lines show a biphasic response, suggesting more than one mechanism of action. Mitochondrial genome-knockout ρ(0) cell lines are insensitive to mycothiazole, supporting a conditional mitochondrial site of action. Mycothiazole is cytostatic rather than cytotoxic in sensitive cells, has a long lag period of about 12 h, and unlike the complex I inhibitor, rotenone, does not cause G(2)/M cell cycle arrest. Mycothiazole decreases, rather than increases the levels of reactive oxygen species after 24 h. It is concluded that the cytostatic inhibitory effects of mycothiazole on mitochondrial electron transport function in sensitive cell lines may depend on a pre-activation step that is absent in insensitive cell lines with intact mitochondria, and that a second lower-affinity cytotoxic target may also be involved in the metabolic and growth inhibition of cells.
Kirsten J Meyer; A Jonathan Singh; Alanna Cameron; An S Tan; Dora C Leahy; David O'Sullivan; Praneta Joshi; Anne C La Flamme; Peter T Northcote; Michael V Berridge; John H Miller
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-04-16
Journal Detail:
Title:  Marine drugs     Volume:  10     ISSN:  1660-3397     ISO Abbreviation:  Mar Drugs     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-06-12     Completed Date:  2012-11-26     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101213729     Medline TA:  Mar Drugs     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  900-17     Citation Subset:  IM    
Centre for Biodiscovery and Schools of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand.
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MeSH Terms
Aquatic Organisms / chemistry,  metabolism
Cell Cycle / drug effects
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Electron Transport Complex I / antagonists & inhibitors*
Genome, Mitochondrial*
HL-60 Cells
HeLa Cells
Jurkat Cells
Mitochondria / drug effects*,  genetics,  metabolism*
Porifera / chemistry,  metabolism
Reactive Oxygen Species / metabolism
Thiazoles / pharmacology*
Reg. No./Substance:
0/Reactive Oxygen Species; 0/Thiazoles; 0/mycothiazole; EC Transport Complex I

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