We have previously reported that
adenosine triphosphate (
ATP) enhances the cytotoxic effects of
4-hydroperoxycyclophosphamide (4HC) on
leukemia cells without affecting the normal hematopoietic stem cells. Increased cell membrane permeability induced by
ATP may cause high incorporation of 4HC into
leukemia cells, ultimately leading to cell death. In the present study, we show that
ATP has cytotoxicity against PC14, a
lung adenocarcinoma cell line. When PC14 cells were cultured with 1, 3, and 5 mM
ATP, colony number significantly decreased to 91.0, 48.8, and 2.3% respectively, compared to untreated controls. Additionally,
ATP enhanced the antitumor effects of
etoposide (
VP16) in PC14 and another
lung adenocarcinoma cell line, A549. With 5, 25, and 50 mM
VP16, the percentage of colony numbers compared to control was 95.5, 75.8, and 61.3% in PC14 and 86.0, 65.0, and 57.1% in A549 cells, respectively. In the presence of 3 mM
ATP, however, the colony number of PC14 was further limited to 49.6, 34.1, and 24.4% of the untreated level in 5, 25, and 50 mM
VP16, respectively. When A549 cells were incubated with 1 mM
ATP, the proportion of clonogeneic cells significantly fell to 62.5, 41.7, and 31.7% in 5, 25, and 50 mM
VP16, respectively. With 3 and 5 mM of
ATP, uptake of [3H]
VP16 in PC14 cells increased respectively to 8.9- and 14.1-fold of the negative controls. These results suggest that
ATP itself has antitumor effects on
lung cancer cells and enhances the cytotoxicity of
VP16 through the increased uptake of
VP16 into the cells. The combined use of
ATP and
antitumor agents such as
VP16 may have the potential to improve the therapeutic index in human lung
carcinoma.