(64)Cu-ATSM Predicts Efficacy of Carbon Ion Radiotherapy Associated with Cellular Antioxidant Capacity

SIMPLE SUMMARY: Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. Here we show that the carbon ion RBE in human cancer cells correlates with the cellular uptake of (64)Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) ((64)Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. High RBE/(64)Cu-ATSM cells show greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/(64)Cu-ATSM counterparts. These data suggest that the cellular antioxidant activity is a possible determinant of carbon ion RBE predictable by (64)Cu-ATSM uptake. ABSTRACT: Carbon ion radiotherapy is an emerging cancer treatment modality that has a greater therapeutic window than conventional photon radiotherapy. To maximize the efficacy of this extremely scarce medical resource, it is important to identify predictive biomarkers of higher carbon ion relative biological effectiveness (RBE) over photons. We addressed this issue by focusing on cellular antioxidant capacity and investigated (64)Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) ((64)Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with (64)Cu-ATSM uptake both in vitro and in vivo. High RBE/(64)Cu-ATSM cells showed greater steady-state levels of antioxidant proteins and increased capacity to scavenge reactive oxygen species in response to X-rays than low RBE/(64)Cu-ATSM counterparts; this upregulation of antioxidant systems was associated with downregulation of TCA cycle intermediates. Furthermore, inhibition of nuclear factor erythroid 2-related factor 2 (Nrf2) sensitized high RBE/(64)Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/(64)Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by (64)Cu-ATSM uptake. These new findings highlight the potential clinical utility of (64)Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.