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Hyperbaric oxygen enhanced mitochondria-targeted chemotherapy in bladder cancer
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  • weibing Li,
  • chongxing Shen,
  • xiaofeng Yue,
  • linyong Dai,
  • jianwu Wang,
  • jinjin Li,
  • qiang Fang,
  • yi Zhi,
  • chunmeng shi
weibing Li
Chongqing Medical University
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chongxing Shen
Chongqing Medical University
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xiaofeng Yue
Chongqing Medical University
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linyong Dai
Chongqing Medical University
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jianwu Wang
Chongqing Medical University
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jinjin Li
Chongqing Medical University
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qiang Fang
Chongqing Medical University
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yi Zhi
Chongqing Medical University
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chunmeng shi
State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Rocket Force Medicine, Third Military Medical University
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Abstract

Background and Purpose: Bladder cancer has a high rate of recurrence and drug resistance due to a 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. In the study, we aimed to investigate the anti-tumor effect of IR-780 combined with hyperbaric oxygen (HBO) on bladder cancer. Experimental Approach: Using in vitro cell line data, in vivo model data and clinical data, we tested the ability of IR-780 to selectively accumulate in bladder cancer. We also evaluated the anti-tumor effect of IR-780 combined or not with HBO both in vitro and in vivo, and explored the potential mechanism of its anti-tumor effect. Key Results: We revealed for the first time that IR-780 selectively accumulated in bladder cancer (bladder cancer cells, xenografts and bladder cancer samples from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. Further study displayed that the combination with HBO could significantly enhance the antitumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial reactive oxygen species (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 and Implications: These data identify 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.