Cancer phototherapy via selective photoinactivation of respiratory chain oxidase to trigger a fatal superoxide anion burst

Aims: Here, we develop a novel cancer treatment modality using mitochondria-targeting, high-fluence, low-power laser irradiation (HF-LPLI) in mouse tumor models and explore the mechanism of mitochondrial injury by HF-LPLI. Results: We demonstrated that the initial reaction after photon absorption was photosensitization of cytochrome c oxidase (COX), to inhibit enzymatic activity of COX in situ and cause respiratory chain superoxide anion (O₂ ^-•) burst. We also found that HF-LPLI exerted its main tumor killing effect through mitochondrial O₂^-• burst via electron transport chain (ETC). These phenomena were completely absent in the respiration-deficient cells and COX knockdown cells. With a carefully selected irradiation protocol, HF-LPLI could efficaciously destroy tumors. The inhibition of enzymatic activity of COX and generation of O₂^-• by HF-LPLI in vivo were also detected. Innovation: It is the first time that the mechanism involved in the interaction between light and its photoacceptor under HF-LPLI treatment is clarified. Our results clearly indicate that HF-LPLI initiates its effects via targeted COX photoinactivation and that the tumor-killing efficacy is dependent of the subsequent mitochondrial O ₂^-• burst via ETC. Conclusion: Based on both in vitro and in vivo results, we conclude that HF-LPLI can selectively photoinactivate respiratory chain oxidase to trigger a fatal mitochondrial O₂ ^-• burst, producing oxidative damage on cancer cells. This study opens up the possibilities of applications of HF-LPLI as a mitochondria- targeting cancer phototherapy. Antioxid. Redox Signal. 20, 733-746.