Cancer PhototherapyviaSelective Photoinactivation of Respiratory Chain Oxidase to Trigger a Fatal Superoxide Anion Burst

Abstract

Aims: Here, we develop a novel cancer treatment modality using mitochondria-targeting, high-fluence, lowpower 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 (O 2 -) burst. We also found that HF-LPLI exerted its main tumor killing effect through mitochondrial O 2 -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 O 2 -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 O 2 -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][734][735][736][737][738][739][740][741][742][743][744][745][746]

Proposed Mechanisms of Photobiomodulation or Low-Level Light Therapy

“…Several lines of evidence show that Cox acts as a photoacceptor and transducer of photosignals in the red and near-infrared regions of the light spectrum [28]. It seems that PBM increases the availability of electrons for the reduction of molecular oxygen in the catalytic center of Cox, increasing the mitochondrial membrane potential (MMP) and the levels of ATP, cAMP and ROS as well [29]. …”

“…The evidence is based on the inactivation of caspase-8, activation of caspase-9 and by the release of cytochrome C. When this high dose is used, light inactivates Cox (instead of activating Cox), inducing a superoxide burst in the electron transport chain and, finally, produces oxidative damage against cancer cells [29]. Chu and co-workers already observed that PBM could induce a mitochondrial permeability pore transition when higher levels of ROS are produced.…”

Photodynamic Therapy: Current Status and Future Directions

“…All other conditions being equal, PSs that localize to mitochondria induce apoptotic cell death within a certain threshold of oxidative stress. Particularly with mitochondria, apoptotic cell death can ensue not only from oxidative damage induced by primary, photo-degenerated ROS, but also by superoxide anion generated as a secondary product due to photodamage of components of the electron transport chain [123]. In contrast, PSs targeting lysosomes either delay or block the apoptotic program, thus predisposing the cells to necrosis.…”

Direct 1O2 optical excitation: A tool for redox biology

“…Several experimental aspects are detailed in each entry (see footnotes for more information). Each set of conditions has been obtained from a publication, with the particular reference provided in each case. Transition Biological model Light source Wavelength Power Spectral control 1 O 2 scavenging 1 O 2 enhancement Thermal control Reference 633 nm Human erythrocytesDye laser (pulsed)633 nm–YesNoNoNo[108]Human erythrocytesHe-Ne laser (cw)632.8 nm38–50 mWNopArpO 2 Yes[108]NC-37 lymphoblast lineHe-Ne laser (cw)633 nm1.2 mWNoNoNoNo[177]A2058 melanoma lineHe-Ne laser (cw)632.8 nm7 mWNoNoNoYes[178]Human skin fibroblastsHe-Ne laser (cw)632.8 nm18.8 mWYesNoNoYes[143]MCF-7 breast cancer lineHe-Ne laser (cw)632.8 nm14 mWNoNoNoNo[141]-A549Diode laser (cw)635 nm–No-SODNoNo[181]-EMT6-NAC-ASTC-a-1-EMT6 tumors in miceDiode laser (cw)635 nm–NoNoNoNo[181]-ASTC-a-1 tumors in mice-A549 adenocarcinomaLED (cw)637±17 nm–YesNoNoYes[146]-PtK2 renal line-U2OS osteosarcomaClinical trials in womenDiode laser (cw)…”