Abstract
Treatment failure caused by a radiation-resistant cell phenotype remains an impediment to the success of radiation therapy in cancer. We recently showed that a radiation-resistant isogenic line of human A549 lung cancer cells had significantly elevated expression of hypoxia-inducible factor (HIF-1α), and increased glucose catabolism compared with the parental, radiation-sensitive cell line. The objective of this study was to investigate the longitudinal metabolic changes in radiation-resistant and sensitive A549 lung cancer cells after treatment with a combination of radiation therapy and YC-1, a potent HIF-1 inhibitor. Using label-free two-photon excited fluorescence microscopy, we determined changes in the optical redox ratio of FAD/(NADH and FAD) over a period of 24 hours following treatment with YC-1, radiation, and both radiation and YC-1. To complement the optical redox ratio, we also evaluated changes in mitochondrial organization, glucose uptake, reactive oxygen species (ROS), and reduced glutathione. We observed significant differences in the optical redox ratio of radiation-resistant and sensitive A549 cells in response to radiation or YC-1 treatment alone; however, combined treatment eliminated these differences. Our results demonstrate that the optical redox ratio can elucidate radiosensitization of previously radiation-resistant A549 cancer cells, and provide a method for evaluating treatment response in patient-derived tumor biopsies.
Highlights
Radiation therapy is a critical first line of care that is used to treat the majority of cancer patients[1]
A decrease in the oxidation (redox) ratio (ORR) due to a buildup of NADH that is not converted to NAD+ can be produced by conditions that decrease the rate of oxidative phosphorylation, such as hypoxia or conditions that increase the rate of glucose catabolism, such as macromolecular synthesis[14]
Our results demonstrate an increase in the ORR of A549RR cells, indicating a reduction in glucose catabolism, when treated with YC-1
Summary
Radiation therapy is a critical first line of care that is used to treat the majority of cancer patients[1]. As a regulator of oxygen homeostasis, HIF-1α plays a key role in downregulating mitochondrial oxygen consumption and enhancing transcription of important glycolytic genes such as pyruvate dehydrogenase kinase (PDK-1)[8,9] For this reason, pharmaceutical approaches targeting HIF-1α have shown promise in sensitizing radiation-resistant cancer cells to radiotherapy[10]. We lack an understanding of the time-dependent changes in ORR in response to targeted therapies, either alone or in combination with radiation, and how these changes might manifest in radiation-resistant versus sensitive cells The purpose of this investigation was to identify the acute redox changes in radiation-resistant lung cancer cells treated with a radiosensitizing HIF-1α inhibitor. Understanding how changes in the cellular redox state in the post-radiation environment are confounded by drug treatment provides a basis for label-free optical imaging to determine how patients might respond to chemoradiation therapy even before they commence treatment
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