Increased tumour extracellular pH induced by Bafilomycin A1 inhibits tumour growth and mitosis in vivo and alters 5-fluorouracil pharmacokinetics.
The aim was to determine if a specific inhibitor of vacuolar H(+)-ATPases (V-ATPases), Bafilomycin A1 (BFM), could increase the low extracellular pH (pHe) typical of solid tumours and thus inhibit their growth in vivo. BFM inhibited the proliferation of various human cells and rat pituitary GH3 tumour cells in vitro (IC50: 2.5-19.2 nM), and flow cytometry on GH3 cells showed a marked increase in S and G2M phases after 16-48 h, but no evidence of increased apoptosis. BFM caused significant inhibition of GH3 xenograft growth, and histomorphometry showed a 30% decrease in mitosis but no change in apoptosis. 31P-magnetic resonance spectroscopy (MRS) in vivo of GH3 xenografts showed that BFM increased pHe, but did not affect pHi, resulting in a decrease in the negative pH gradient (-delta pH). BFM decreased lactate formation suggesting a reduction in glycolysis. We suggest that BFM reduces extracellular H(+)-transport by inhibition of V-ATPases leading to an increase in pHe and decreased glycolysis, and thus reduced tumour cell proliferation. 19F-MRS in vivo showed that a smaller -delta pH was associated with decreased retention of 5-fluorouracil (5FU) which was consistent with our previous data in vivo implying the -delta pH controls tumour retention of 5 FU.
Cancer Research UK Biomedical Magnetic Resonance Research Group, Department of Biochemistry and Immunology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK. paul_mj.mcsheehy@pharma.novartis.com
P M J
PM
McSheehy
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Troy
L R
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Kelland
I R
IR
Judson
M O
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Leach
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Griffiths
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D002455:Cell Division / Q000187:drug effects; D005472:Fluorouracil / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D018942:Macrolides; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000964:Antimetabolites, Antineoplastic; D018942:Macrolides; C040929:bafilomycin A1; D005472:Fluorouracil