As the modulation of autophagic processes can be therapeutically beneficial to cancer treatment, the identification of novel autophagic enhancers is highly anticipated.
However, current autophagy-inducing anticancer agents exert undesired side effects owing to their non-specific biodistribution in off-target tissues.
Dr Huang and colleagues from China developed a multifunctional agent to integrate cancer targeting, imaging and therapy and to investigate its mechanism.
A series of mitochondria-targeting near-infrared fluorophores were synthesized, screened and identified for their autophagy-enhancing activity.
The optical properties and biological effects were tested both in vitro and in vivo.
The research team investigated the underlying mechanism using inhibitors, small interfering ribonucleic acid, ribonucleic acid sequencing, mass spectrometry and human samples.
The doctors have screened and identified a new near-infrared autophagy-enhancer, IR-58, which exhibits significant tumor-selective killing effects.
IR-58 preferentially accumulates in the mitochondria of colorectal cancer cells and xenografts, a process that is glycolysis-dependent and organic anion transporter polypeptide-dependent.
IR-58 exhibits tumor-selective killing effects
The team found that IR-58 kills tumor cells and induces apoptosis via inducing excessive autophagy, which is mediated through the reactive oxygen species-Akt-mammalian target of rapamycin pathway.
Ribonucleic acid sequencing, mass spectrometry and small interfering ribonucleic acid interference studies demonstrate that translocase of inner mitochondrial membrane 44-superoxide dismutase 2 pathway inhibition is responsible for the excessive reactive oxygen species, autophagy and apoptosis induced by IR-58.
The researchers observed that translocase of inner mitochondrial membrane 44 expression correlates positively with colorectal cancer development and poor prognosis in patients.
Dr Huang's team concluded, "A novel near-infrared small-molecule autophagy-enhancer, IR-58, with mitochondria-targeted imaging and therapy capabilities was developed for colorectal cancer treatment."
"Additionally, translocase of inner mitochondrial membrane 44 was identified for the first time as a potential oncogene, which plays an important role in autophagy through the translocase of inner mitochondrial membrane 44-Superoxide dismutase 2, mitochondrial-reactive oxygen species-Akt-mammalian target of rapamycin pathway."