TY - JOUR
T1 - The farnesyltransferase inhibitor manumycin A is a novel trypanocide with a complex mode of action including major effects on mitochondria
AU - Ali, Bassam R.S.
AU - Pal, Arun
AU - Croft, Simon L.
AU - Taylor, Richard J.K.
AU - Field, Mark C.
N1 - Funding Information:
We are very grateful to the following for advice and reagents; M. Carrington (EATRO 1175 strain), P. Mastroeni (FACS analysis) and H. Field (TbRab microscopy and comments on the manuscript). This work was supported by the MRC (Project Grant #G9624235 to M.C. Field).
PY - 1999/10/25
Y1 - 1999/10/25
N2 - Eukaryotes modify numerous proteins, including small GTPases of the ras superfamily, with isoprenes as a mechanism for membrane attachment. Inhibition of farnesylation of ras has been successfully exploited to control cell growth, with promise in the clinic for treatment of human tumours. Using an in vitro screen of mammalian farnesyltransferase inhibitors, we have identified manumycin A as potently active against growth of both bloodstream and procyclic forms of Trypanosoma brucei. Other structural classes of farnesyltransferase inhibitors were far less effective. Exposure of T. brucei for brief periods to lethal concentrations of manumycin A resulted in subsequent cell death whilst the concentration required to achieve killing was dependent on serum concentration, suggesting partitioning of manumycin A into hydrophobic cellular sites. Manumycin A did not affect trypanosomal protein and DNA synthesis or cell cycle progression but altered incorporation of prenyl groups into several polypeptides indicating a specific effect on the prenylation without effect on other mevalonate pathway products, most importantly prenyl pyrophosphate levels. Morphological analysis indicated that manumycin A caused significant mitochondrial damage suggesting an additional site of action. Structural analogues of manumycin A containing a quinone were also highly trypanocidal and altered mitochondrial morphology, suggesting interference with electron/proton transport systems. Furthermore, manumycin A also elicited mitochondrial alterations in mammalian cells indicating that the effect is not confined to lower eukaryotes. Manumycin A is well tolerated in vivo but failed to cure experimental trypanosomiasis in mice.
AB - Eukaryotes modify numerous proteins, including small GTPases of the ras superfamily, with isoprenes as a mechanism for membrane attachment. Inhibition of farnesylation of ras has been successfully exploited to control cell growth, with promise in the clinic for treatment of human tumours. Using an in vitro screen of mammalian farnesyltransferase inhibitors, we have identified manumycin A as potently active against growth of both bloodstream and procyclic forms of Trypanosoma brucei. Other structural classes of farnesyltransferase inhibitors were far less effective. Exposure of T. brucei for brief periods to lethal concentrations of manumycin A resulted in subsequent cell death whilst the concentration required to achieve killing was dependent on serum concentration, suggesting partitioning of manumycin A into hydrophobic cellular sites. Manumycin A did not affect trypanosomal protein and DNA synthesis or cell cycle progression but altered incorporation of prenyl groups into several polypeptides indicating a specific effect on the prenylation without effect on other mevalonate pathway products, most importantly prenyl pyrophosphate levels. Morphological analysis indicated that manumycin A caused significant mitochondrial damage suggesting an additional site of action. Structural analogues of manumycin A containing a quinone were also highly trypanocidal and altered mitochondrial morphology, suggesting interference with electron/proton transport systems. Furthermore, manumycin A also elicited mitochondrial alterations in mammalian cells indicating that the effect is not confined to lower eukaryotes. Manumycin A is well tolerated in vivo but failed to cure experimental trypanosomiasis in mice.
KW - Chemotherapy
KW - Farnesyltransferase
KW - Small GTPases
KW - Trypanosomiasis
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U2 - 10.1016/S0166-6851(99)00131-0
DO - 10.1016/S0166-6851(99)00131-0
M3 - Article
C2 - 10589982
AN - SCOPUS:0032746383
SN - 0166-6851
VL - 104
SP - 67
EP - 80
JO - Molecular and Biochemical Parasitology
JF - Molecular and Biochemical Parasitology
IS - 1
ER -