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. 2019 Oct 2;9:14210. doi: 10.1038/s41598-019-50291-0

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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CAP and PAM-mediated apoptosis induction in tumor cells. (a) CAP- and PAM-mediated apoptosis induction in tumor cells is dependent on singlet oxygen (¹O₂). A-D: Treatment with CAP. MKN-45 tumor cells in medium were treated with CAP for either 20 sec or 1 min, either in the absence of the ¹O₂ scavenger histidine (HIS) (2 mM) or with HIS addition at the indicated times. Control assays were not treated with CAP. The percentages of apoptotic cells were determined after 2 and 5 h. E,F: The effect of PAM. Medium was treated with CAP for 20 or 60 sec, or not treated. It was then added to an equal volume of MKN-45 cells at double standard density, in the absence or presence of HIS. The final volume was 100 µl. The percentages of apoptotic cells were determined after 2 and 5 h. These results show that ¹O₂ generated by long-lived species that are generated through treatment of medium with CAP are sufficient to trigger apoptosis induction in tumor cells. The ¹O₂-dependent process seems to be completed within less than half an hour. Statistical analysis: Apoptosis induction by CAP or PAM under all conditions is highly significant (p < 0.001). The inhibition by histidine added a 0 or 2 min is highly significant (p < 0.001) in all assays. The differences between the effect of histidine added at 20 min or 0/2 min is highly significant (p < 0.001). (b) CAP-mediated apoptosis induction in tumor cells: Dependency on singlet oxygen (¹O₂), peroxynitrite (ONOO⁻), superoxide anions (O₂^⋅−) and aquaporins. MKN-45 tumor cells were treated with CAP in the absence or presence of the indicated scavengers/inhibitors (A: the ¹O₂ scavenger histidine (HIS) (2 mM); B: the ONOO⁻ decomposition catalyst FeTPPS (25 µM); C: the NOX1 inhibitor AEBSF (100 µM); D: the aquaporine inhibitor Ag⁺ (5 µM)). Scavengers/inhibitors had been added either 10 min before CAP treatment, or 2 min or 20 min after CAP treatment. The percentages of apoptotic cells were determined after 4.5 h. These results show that CAP-mediated apoptosis induction in tumor cells involves a very fast ¹O₂ - and ONOO⁻-dependent process, as well as longer-lasting processes in which superoxide anions and aquaporins are involved. Statistical analysis: Apoptosis induction by CAP is highly significant (p < 0.001). Inhibition of CAP-mediated apoptosis induction by histidine and FeTPPS added at −10 or 2 min, as well as inhibition by AEBSF or Ag⁺, added at all time points, is highly significant (p < 0.001).