Cell type-specific effects of Adenosine 5′-triphosphate and pyrophosphate on the antitumor activity of doxorubicin

Jang Shiun Wang, Yeo Loo Chang, Yang Hao Yu, Chih Yi Chen, Ming Ching Kao, Tsai Kun Li, Wan Wan Lin

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1811-1819
Number of pages9
JournalCancer Science
Volume103
Issue number10
DOIs
Publication statusPublished - Oct 2012

Fingerprint

Doxorubicin
Adenosine Diphosphate
Adenosine Triphosphate
DNA Damage
Lung Neoplasms
Purinergic P2 Receptor Antagonists
Poly Adenosine Diphosphate Ribose
Neoplasms
Type II DNA Topoisomerase
Uridine Triphosphate
Comet Assay
Uridine Diphosphate
Cytoprotection
Propidium
Osteosarcoma
Caspases
Caspase 3
Uterine Cervical Neoplasms
Colonic Neoplasms
Reactive Oxygen Species

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Wang, J. S., Chang, Y. L., Yu, Y. H., Chen, C. Y., Kao, M. C., Li, T. K., & Lin, W. W. (2012). Cell type-specific effects of Adenosine 5′-triphosphate and pyrophosphate on the antitumor activity of doxorubicin. Cancer Science, 103(10), 1811-1819. https://doi.org/10.1111/j.1349-7006.2012.02376.x

Cell type-specific effects of Adenosine 5′-triphosphate and pyrophosphate on the antitumor activity of doxorubicin. / Wang, Jang Shiun; Chang, Yeo Loo; Yu, Yang Hao; Chen, Chih Yi; Kao, Ming Ching; Li, Tsai Kun; Lin, Wan Wan.

In: Cancer Science, Vol. 103, No. 10, 10.2012, p. 1811-1819.

Research output: Contribution to journalArticle

Wang, Jang Shiun ; Chang, Yeo Loo ; Yu, Yang Hao ; Chen, Chih Yi ; Kao, Ming Ching ; Li, Tsai Kun ; Lin, Wan Wan. / Cell type-specific effects of Adenosine 5′-triphosphate and pyrophosphate on the antitumor activity of doxorubicin. In: Cancer Science. 2012 ; Vol. 103, No. 10. pp. 1811-1819.
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