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

Jang-Shiun Wang1, Yeo-Loo Chang, Yang-Hao Yu

  • 1Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Cancer Science
|July 4, 2012
PubMed

Insights

Extracellular ATP generally does not affect doxorubicin

Area of Science:

  • Biochemistry
  • Cell Biology
  • Oncology

Background:

  • Extracellular ATP (adenosine triphosphate) is a signaling molecule with diverse biological roles.
  • While ATP's role in cancer progression is suggested, its impact on chemotherapy effectiveness is not well understood.

Purpose of the Study:

  • To investigate the effect of extracellular ATP on doxorubicin cytotoxicity across various cancer cell types.
  • To elucidate the mechanisms underlying ATP's influence on doxorubicin efficacy in lung cancer cells.

Main Methods:

  • Assessed doxorubicin cytotoxicity in colon, prostate, breast, cervical cancer, osteosarcoma, and lung cancer cell lines (CL1.0 and CL1.5) with and without ATP treatment.
  • Analyzed apoptotic and necrotic markers, including sub-G(1) DNA content, caspase 3 activation, PARP-1 cleavage, propidium iodide uptake, and reactive oxygen species (ROS) production.
  • Evaluated DNA damage using the comet assay and poly(ADP-ribose) formation, and assessed topoisomerase II inhibition.
  • Investigated the role of p53 using the p53 inhibitor pifithrin-α and examined the effects of other nucleotides and P2 receptor antagonists.

Main Results:

  • ATP did not alter doxorubicin cytotoxicity in colon, prostate, breast, cervical cancers, or osteosarcoma.
  • In lung cancer cells, ATP protected CL1.0 cells from doxorubicin-induced apoptosis and necrosis but had no effect on CL1.5 cells.
  • ATP reduced doxorubicin-induced DNA damage, p53 accumulation, and topoisomerase II inhibition in CL1.0 cells, with pyrophosphate mediating this protective effect.

Conclusions:

  • Extracellular ATP generally does not impact doxorubicin's antitumor efficacy across most cancer types.
  • ATP exhibits a protective effect against doxorubicin in non-metastatic lung cancer CL1.0 cells, but not in highly metastatic CL1.5 cells.
  • Pyrophosphate mediates ATP's protective role in CL1.0 cells by attenuating oxidative stress, DNA damage, p53 activation, and apoptosis.

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