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Hyperbaric oxygen enhanced the chemotherapy of mitochondrial targeting molecule IR-780 in bladder cancer
Chongxing Shen1, Xiaofeng Yue1, Linyong Dai1
1Department of Urology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
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.
Insights
A new bladder cancer treatment combines IR-780, a near-infrared agent, with hyperbaric oxygen (HBO). This novel therapy targets mitochondria, enhances tumor cell death, and shows promise against drug-resistant bladder cancer.
Area of Science:
- Oncology
- Biomedical Engineering
- Mitochondrial Biology
Background:
- Bladder cancer frequently recurs and resists treatment due to limited therapeutic options.
- IR-780 iodide, a near-infrared (NIR) agent, targets mitochondria and shows selective tumor-killing potential.
- Its application in bladder cancer therapy remains largely unexplored.
Purpose of the Study:
- To investigate the efficacy of IR-780 iodide as a bladder cancer therapeutic.
- To evaluate the synergistic anti-tumor effects of combining IR-780 with hyperbaric oxygen (HBO).
- To assess the potential of this combination therapy in drug-resistant bladder cancer models.
Main Methods:
- NIR imaging was used to track IR-780 accumulation in bladder cancer.
- Cell viability, apoptosis, ATP production, mitochondrial ROS, and membrane potential were assessed in human bladder cancer cell lines treated with IR-780 and/or HBO.
- Tumor growth and recurrence were evaluated in mouse models, including those with drug-resistant bladder cancer cells (T24/DDP).
Main Results:
- IR-780 selectively accumulated in bladder cancer cells and tumors, inducing apoptosis via mitochondrial complex I (NDUFS1) targeting.
- The combination of IR-780 and HBO significantly enhanced anti-tumor effects in vitro and suppressed tumor growth and recurrence in vivo with minimal toxicity.
- The IR-780 + HBO strategy demonstrated efficacy in both drug-resistant bladder cancer cells and xenografts.
Conclusions:
- The combination of IR-780 and HBO represents a novel, mitochondria-targeting therapeutic approach for bladder cancer.
- This strategy shows significant potential for treating both primary and drug-resistant bladder cancer.
- Further research into IR-780 + HBO could lead to improved bladder cancer treatment paradigms.
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