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H2O2 enhances the anticancer activity of TMPyP4 by ROS-mediated mitochondrial dysfunction and DNA damage

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Abstract

Cancer is one of the diseases that threatens human health and is a leading cause of mortality worldwide. High levels of reactive oxygen species (ROS) have been observed in cancer tissues compared with normal tissues in vivo, and it is not yet known how this influences chemotherapeutic drug action. Cationic porphyrin 5,10,15,20-tetra-(N-methyl-4-pyridyl) porphyrin (TMPyP4) is a photosensitizer used in photodynamic therapy (PDT) and a telomerase inhibitor used in the treatment of telomerase-positive cancer. Here, we investigated the anticancer activity of TMPyP4 in A549 and PANC cells cultured in H2O2. The results showed that compared to TMPyP4 alone, the combination of TMPyP4 and H2O2 exhibited sensitization effects on cell viability and colony formation inhibition and apoptosis in A549 and PANC cells, but had no effect in human normal MIHA cells. Mechanistically, the combination of TMPyP4 and H2O2 activates high ROS and mitochondrial membrane potential in A549 and PANC cells, resulting in intense DNA damage and DNA damage responses. Consequently, compared to TMPyP4 alone, TMPyP4 and H2O2 combined treatment upregulates the expression of BAX, cleaved caspase 3, and p-JNK and downregulates the expression of Bcl-2 in A549 and PANC cells. Taken together, these data suggested that H2O2 enhanced the anticancer activity of TMPyP4-mediated ROS-dependent DNA damage and related apoptotic protein regulation, revealing that the high ROS tumor microenvironment plays an important role in chemotherapeutic drug action.

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Abbreviations

TME:

Tumor microenvironment

ROS:

Reactive oxygen species

PDT:

Photodynamic therapy

TMPyP4:

5,10,15,20-Tetra-(N-methyl-4-pyridyl) porphyrin

PDT:

Photodynamic therapy

MTT:

3‑(4,5‑Dimethyl‑2‑thiazolyl)‑2,5‑diphenyl‑2‑H‑tetrazolium bromide

FCM:

Flow cytometry

IF:

Immunofluorescence

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Acknowledgements

We thank Elsevier (http://webshop.elsevier.com/languageediting/) for its linguistic assistance during the preparation of this manuscript.

Funding

The present study was funded by National Science Foundation of China (Grant No.: 21701194), Wenzhou Basic Medical and Health Technology Project (Grant No.: Y20180177), and Wenzhou Medical University Talent Start-up Fund (Grant No.: QTJ17022) for the financial support.

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Authors and Affiliations

  1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, People’s Republic of China

    Jianqiang Chen, Xiangxiang Jin, Zhe Shen, Yanan Mei, Jufan Zhu, Guang Liang & Xiaohui Zheng

  2. Department of Pharmacy, The Seventh People’s Hospital of Wenzhou, Wenzhou, 325006, Zhejiang, People’s Republic of China

    Xiaodan Zhang

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  1. Jianqiang Chen
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Contributions

Conceptualization: XHZ, GL, XDZ, and JQC. Methodology and Data analysis: JQC, XXJ, ZS, YM, and JFZ. Writing—original draft preparation: XZ and JC. Funding acquisition and supervision: XHZ, GL, and XDZ.

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Correspondence to Xiaodan Zhang, Guang Liang or Xiaohui Zheng.

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Chen, J., Jin, X., Shen, Z. et al. H2O2 enhances the anticancer activity of TMPyP4 by ROS-mediated mitochondrial dysfunction and DNA damage. Med Oncol 38, 59 (2021). https://doi.org/10.1007/s12032-021-01505-x

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