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.