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