TY - JOUR
T1 - 64cu-atsm predicts efficacy of carbon ion radiotherapy associated with cellular antioxidant capacity
AU - Nachankar, Ankita
AU - Oike, Takahiro
AU - Hanaoka, Hirofumi
AU - Kanai, Ayaka
AU - Sato, Hiro
AU - Yoshida, Yukari
AU - Obinata, Hideru
AU - Sakai, Makoto
AU - Osu, Naoto
AU - Hirota, Yuka
AU - Takahashi, Akihisa
AU - Shibata, Atsushi
AU - Ohno, Tatsuya
N1 - Funding Information:
Acknowledgments: This work was the result of using research equipment shared in the MEXT Project for promoting public utilization of advanced research infrastructure (Program for supporting the introduction of the new sharing system) Grant Number JPMXS0420600120.
Funding Information:
This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan for programs for Leading Graduate Schools, Cultivating Global Leaders in Heavy Ion Therapeutics and Engineering. This work was also supported by Gunma University Heavy Ion Medical Center.Acknowledgments: This work was the result of using research equipment shared in the MEXT Project for promoting public utilization of advanced research infrastructure (Program for supporting the introduction of the new sharing system) Grant Number JPMXS0420600120.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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 investigated64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-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/64Cu-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/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by64Cu-ATSM uptake. These new findings highlight the potential clinical utility of64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.
AB - 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 investigated64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM), a potential radioligand that reflects an over-reduced intracellular environment. We found that the carbon ion RBE correlated with64Cu-ATSM uptake both in vitro and in vivo. High RBE/64Cu-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/64Cu-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/64Cu-ATSM cells to X-rays, thereby reducing RBE values to levels comparable to those in low RBE/64Cu-ATSM cells. These data suggest that the cellular activity of Nrf2-driven antioxidant systems is a possible determinant of carbon ion RBE predictable by64Cu-ATSM uptake. These new findings highlight the potential clinical utility of64Cu-ATSM imaging to identify high RBE tumors that will benefit from carbon ion radiotherapy.
KW - 64Cu-ATSM
KW - Antioxidant sys-tems
KW - Carbon ion radiotherapy
KW - Reactive oxygen species
KW - Relative biological effectiveness
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U2 - 10.3390/cancers13246159
DO - 10.3390/cancers13246159
M3 - Article
AN - SCOPUS:85120629221
SN - 2072-6694
VL - 13
JO - Cancers
JF - Cancers
IS - 24
M1 - 6159
ER -
