-Clinical significance
The
combination of IR-780 and
hyperbaric
oxygen was identified as a novel treatment paradigm for bladder cancer.
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.
Keywords :
Bladder
cancer, drug-resistant,
IR-780
dye, HBO, mitochondria-targeting