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Mitochondrial Genome-Knockout Cells Demonstrate a Dual Mechanism of Action for the Electron Transport Complex I Inhibitor Mycothiazole
Centre for Biodiscovery and Schools of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
Centre for Biodiscovery and School of Chemical and Physical Sciences, Victoria University of Wellington, PO Box 600, Wellington, New Zealand
Malaghan Institute of Medical Research, Wellington, New Zealand
* Author to whom correspondence should be addressed.
Received: 19 March 2012; in revised form: 10 April 2012 / Accepted: 12 April 2012 / Published: 16 April 2012
Abstract: 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 (IC50 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 (IC50 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 ρ0 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 G2/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.
Keywords: metabolic inhibitor; mitochondrial electron transport complex I; mycothiazole; natural product; reactive oxygen species
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Meyer, K.J.; Singh, A.J.; Cameron, A.; Tan, A.S.; Leahy, D.C.; O’Sullivan, D.; Joshi, P.; La Flamme, A.C.; Northcote, P.T.; Berridge, M.V.; Miller, J.H. Mitochondrial Genome-Knockout Cells Demonstrate a Dual Mechanism of Action for the Electron Transport Complex I Inhibitor Mycothiazole. Mar. Drugs 2012, 10, 900-917.
Meyer KJ, Singh AJ, Cameron A, Tan AS, Leahy DC, O’Sullivan D, Joshi P, La Flamme AC, Northcote PT, Berridge MV, Miller JH. Mitochondrial Genome-Knockout Cells Demonstrate a Dual Mechanism of Action for the Electron Transport Complex I Inhibitor Mycothiazole. Marine Drugs. 2012; 10(4):900-917.
Meyer, Kirsten J.; Singh, A. Jonathan; Cameron, Alanna; Tan, An S.; Leahy, Dora C.; O’Sullivan, David; Joshi, Praneta; La Flamme, Anne C.; Northcote, Peter T.; Berridge, Michael V.; Miller, John H. 2012. "Mitochondrial Genome-Knockout Cells Demonstrate a Dual Mechanism of Action for the Electron Transport Complex I Inhibitor Mycothiazole." Mar. Drugs 10, no. 4: 900-917.