Increased tumour extracellular pH induced by Bafilomycin A 1 inhibits tumour growth and mitosis in vivo and alters 5-fluorouracil pharmacokinetics

Abstract

The aim was to determine if a specific inhibitor of vacuolar H +-ATPases (V-ATPases), Bafilomycin A 1 (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 (IC 50: 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 (-ΔpH). 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 -ΔpH was associated with decreased retention of 5-fluorouracil (5FU) which was consistent with our previous data in vivo implying the -ΔpH controls tumour retention of 5FU.