Introduction
Bladder cancer is the ninth most common cancer in the world and one of
the costliest cancers to manage due to the multiple therapeutic
interventions needed (Svatek et al.,
2014).
Approximately 75% of newly diagnosed patients presents with
non-muscle-invasive
bladder cancer (NMIBC). Although the 5-year survival rate of NMIBC is
over 80%, the recurrence rate after initial treatment can reach up to
70% (Ploeg, Aben & Kiemeney, 2009), which brings physical pain to
patients and a high cost of treatment to patients’ families and society.
Cisplatin-based chemotherapy is currently a standard treatment for
muscle-invasive and metastatic bladder cancer (Alfred Witjes et al.,
2017).
However,
the
subsequent survival benefits can only be described as modest due to
chemoresistance.
Despite
efforts to improve surgical techniques and systemic treatment, the
prognosis of bladder cancer has not changed over the past 20 years due
to
a
lack of effective therapies (Zehnder et al., 2013),
underscoring
the need for new agents to reduce the recurrence of bladder cancer and
drug resistance.
Mitochondria, which play a pivotal role in the regulation of
tumorigenesis and progression, have recently attracted increasing
attention as the subcellular target suitable for cancer therapy (WX, JD
& E, 2016).
Targeting
mitochondria
in cancer cells may provide new strategy to tumor-targeting therapy,
especially for drug-resistant cancer cells, which may be more dependent
on mitochondria (JR et al., 2018; Y et al.,
2019).
However,
this mitochondria-targeted treatment strategy is rarely studied in
bladder cancer. The practical application of current
mitochondrial-targeted therapy is limited due to the poor tumor-specific
distribution and reduced drug accumulation in
mitochondria.
Recently,
a
couple of near infrared heptamethine dyes with both tumor and
mitochondrial targeting have attracted much attention. IR-780 iodide,
a
near-infrared
(NIR)
fluorescent
agent,
has
been reported to achieve
higher
selectivity than other drugs for
the
mitochondria of
different
types of tumor cells and xenografts (Zhang et al., 2010). In addition,
IR-780 has an absorption peak at 780 nm and can emit fluorescence with a
high intensity in the 807-823 nm wavelength range, which facilitates its
use for imaging applications (Kuang et al., 2017). However,
research
on the anti-tumor effect and mechanism of IR-780 is limited. In the
current study, we revealed for the first time that IR-780 selectively
accumulated in bladder cancer and can induce cancer cell apoptosis by
targeting the mitochondrial electron transfer chain (ETC).
Further
research found that combined treatment with IR-780 and HBO exerted an
incredible antitumor effect, representing a novel candidate strategy for
bladder cancer-targeted therapy.
Materials
andMethods