Cell type-specific effects of Adenosine 5′-triphosphate and pyrophosphate on the antitumor activity of doxorubicin
Journal
Cancer Science
Journal Volume
103
Journal Issue
10
Pages
1811-1819
Date Issued
2012
Author(s)
Abstract
Extracellular ATP is an important signaling molecule mediating quite divergent specific biological effects. Even though recent studies suggest a potential role of ATP in cancer progress, its real impact in chemotherapeutic efficacy remains unclear. In the present study, we investigated the effect of ATP on the cytotoxicity of doxorubicin in various cancer cell types and found that ATP had no effect on doxorubicin cytotoxicity in colon, prostate, breast, and cervical cancers or in osteosarcoma. In contrast, ATP has divergent effects on lung cancer cells: it can protect against doxorubicin-induced cell death in non-metastatic lung cancer CL1.0 cells, but not in highly metastatic CL1.5 cells. Both apoptotic (characterized by sub-G1 peak, caspase 3 activation, poly(ADP-ribose) polymerase-1 cleavage) and necrotic (characterized by propidium iodide uptake and ROS production) features induced by doxorubicin in CL1.0 cells were reduced by ATP. In addition, ATP attenuated p53 accumulation, DNA damage (assessed by poly(ADP-ribose) formation and the comet assay) and topoisomerase II inhibition after doxorubicin treatment, and doxorubicin cytotoxicity was diminished by the p53 inhibitor pifithrin-α. Moreover, UTP, UDP, ADP, and pyrophosphate sodium pyrophosphate tetrabasic decahydrate diminished the antitumor effect of doxorubicin in CL1.0 cells, whereas purinergic P2 receptors antagonists did not abrogate the action of ATP. In summary, ATP fails to alter the antitumor efficacy of doxorubicin in most cancer cell types, except in CL1.0 cells, in which pyrophosphate mediates the cell protection afforded by ATP via attenuation of reactive oxygen species production, DNA damage, p53 accumulation, and caspase activation. ? 2012 Japanese Cancer Association.
SDGs
Other Subjects
adenosine triphosphate; caspase 3; DNA topoisomerase (ATP hydrolysing); doxorubicin; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; pifithrin alpha; protein p53; purinergic P2 receptor antagonist; pyrophosphate; reactive oxygen metabolite; antineoplastic activity; apoptosis; article; breast cancer; cancer cell; cell death; cell type; colon cancer; comet assay; controlled study; cytotoxicity; DNA damage; drug efficacy; enzyme activity; lung cancer; osteosarcoma; priority journal; prostate cancer; uterine cervix cancer; Adenosine Triphosphate; Antibiotics, Antineoplastic; Apoptosis; Blotting, Western; Cell Line, Tumor; Cell Survival; Comet Assay; Diphosphates; Doxorubicin; Humans; Necrosis; Real-Time Polymerase Chain Reaction
Type
journal article