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Hyperbaric oxygen enhanced the chemotherapy of mitochondrial targeting molecule IR-780 in bladder cancer

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Bladder cancer has a high rate of recurrence and drug resistance due to the lack of effective therapies. IR-780 iodide, a near-infrared (NIR) mitochondria-targeting fluorescent agent, has been demonstrated to achieve higher selectivity than other drugs in different tumor types and exhibited tumor-killing effects in some cancers. However, this therapeutic strategy is rarely studied in bladder cancer.

Material and methods

The accumulation of IR-780 in bladder cancer was measured by NIR imaging. Human bladder cell lines (T24, 5637, and TCCSUP) were treated with IR-780 or combined IR-780 and hyperbaric oxygen (HBO). Cell viability, cell apoptosis, cellular ATP production, mitochondrial reactive oxygen species (ROS), and plasma membrane potential were detected. Mitochondrial complex I protein NDUFS1 was measured by western blot. To confirm the anti-tumor efficacy of IR-780 + HBO, mouse bladder cell line (MB49) tumor-bearing mice were established and tumor size and weight were recorded. Besides, cell apoptosis and tumor size were assessed in drug-resistant bladder cancer cells (T24/DDP) and xenografts to evaluate the effect of IR-780 + HBO on drug-resistant bladder cancer.

Results

IR-780 selectively accumulated in bladder cancer (bladder cancer cells, transplanted tumors, and bladder cancer tissue from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. The combination with HBO could significantly enhance the anti-tumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial ROS production, while suppressing tumor growth and recurrence in animal models without causing apparent toxicity. Moreover, this combination antitumor strategy was also demonstrated in drug-resistant bladder cancer cells (T24/DDP) and xenografts.

Conclusion

We identified for the first time a combination of IR-780 and HBO (IR-780 + HBO), which exhibits mitochondria-targeting and therapeutic capabilities, as a novel treatment paradigm for bladder cancer.

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Availability of data and materials

The datasets used during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank the neurosurgery department of Southwest Hospital (Chongqing, China) for providing a temperature-adjustable hyperbaric chamber. The manuscript has been presented as “pre-print” with the following link: https://www.researchsquare.com/article/rs-111008/v1.

Funding

This work was supported by National Natural Science Foundation of Chongqing Province (No.cstc 2018jcyjAX0034), National Key Research and Development Program (2016YFC1000805, to C. Shi), National Natural Science Foundation of Chongqing Province (No.cstc 2021 jcyj-bsh0238 to X. Yue), Key research incubation in the Third Affiliated Hospital of Chongqing Medical University (KY08026, to Y. Zhi), Science and technology project of Yubei District, Chongqing (2021-NS-38, to Y. Zhi).

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Author notes

  1. Chongxing Shen and Xiaofeng Yue have equally contributed to this work.

Authors and Affiliations

  1. Department of Urology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China

    Chongxing Shen, Xiaofeng Yue, Linyong Dai, Jianwu Wang, Jinjin Li, Qiang Fang, Yi Zhi & Weibing Li

  2. Institute of Rocket Force Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, 400038, China

    Chunmeng Shi

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  1. Chongxing Shen
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Contributions

LWB & SCM conceived and designed the experiments, supervised the experiments and revised the manuscript. SCX performed the experiments, analyzed the data and drafted the manuscript. YXF and WJW took part in the animal experiments, drafted the manuscript and analysis of optical properties. DLY and LJJ participated in Flow Cytometer and western blot analysis. FQ and ZY contributed to collecting human tissues. All authors have read and approved the final manuscript.

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Correspondence to Yi Zhi, Chunmeng Shi or Weibing Li.

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The collection of human tumor samples and related procedures were approved by the Ethical Committee of the Third Affiliated Hospital, Chongqing Medical University. The animal experiments in our study were conducted in accordance with the Helsinki Declaration and approved by the Laboratory Animal Welfare and Ethics Committee of Third Military Medical University.

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Shen, C., Yue, X., Dai, L. et al. Hyperbaric oxygen enhanced the chemotherapy of mitochondrial targeting molecule IR-780 in bladder cancer. J Cancer Res Clin Oncol 149, 683–699 (2023). https://doi.org/10.1007/s00432-022-04385-4

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