TY - JOUR
T1 - Selenium Modulates Cancer Cell Response to Pharmacologic Ascorbate
AU - Jankowski, Connor S.R.
AU - Rabinowitz, Joshua D.
N1 - Funding Information:
The authors thank Dr. Melanie McReynolds from the Pennsylvania State University for her advice on NAD+ metabolism and PARP inhibitors and Rishabh Sharan for his assistance writing code to facilitate data analysis. This work is supported by grant R01 CA163591 (J.D. Rabinowitz), a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (grant number: SU2C-AACR-DT20-16) and LUSTGARTEN 2015-002 (J.D. Rabinowitz),
Funding Information:
The authors thank Dr. Melanie McReynolds from the Pennsylvania State University for her advice on NADþ metabolism and PARP inhibitors and Rishabh Sharan for his assistance writing code to facilitate data analysis. This work is supported by grant R01 CA163591 (J.D. Rabinowitz), a Stand Up To Cancer-Cancer Research UK-Lustgarten Foundation Pancreatic Cancer Dream Team Research Grant (grant number: SU2C-AACR-DT20-16) and LUSTGARTEN 2015-002 (J.D. Rabinowitz), and by Ludwig Cancer Research. Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. The authors also thank Christine Decoste and Katherine Rittenbach at the Princeton Flow Cytometry Resource Facility. The Princeton University Flow Cytometry Resource Facility is supported, in part, with funding from NCI-CCSG P30CA072720-5921. C.S.R. Jankowski is supported by the NIGMS of the NIH under grant T32GM007388.
Funding Information:
J.D. Rabinowitz reports grants from NIH, NCI, Stand Up To Cancer, Lustgarten Foundation, and Ludwig Cancer Research during the conduct of the study; other support from Colorado Research Partners, Kadmon Pharmaceuticals, L.E.A.F. Pharmaceuticals, Rafael Pharmaceuticals, Empress Therapeutics, Agios Pharmaceuticals, Farber Partners, and Serien Therapeutics; and personal fees from Pfizer outside the submitted work. No disclosures were reported by the other author.
Funding Information:
and by Ludwig Cancer Research. Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. The authors also thank Christine Decoste and Katherine Rittenbach at the Princeton Flow Cytometry Resource Facility. The Princeton University Flow Cytometry Resource Facility is supported, in part, with funding from NCI-CCSG P30CA072720-5921. C.S.R. Jankowski is supported by the NIGMS of the NIH under grant T32GM007388.
Publisher Copyright:
©2022 American Association for Cancer Research.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - High-dose ascorbate (vitamin C) has shown promising anticancer activity. Two redox mechanisms have been proposed: hydrogen peroxide generation by ascorbate itself or glutathione depletion by dehydroascorbate (formed by ascorbate oxidation). Here we show that the metabolic effects and cytotoxicity of high-dose ascorbate in vitro result from hydrogen peroxide independently of dehydroascorbate. These effects were suppressed by selenium through antioxidant selenoenzymes including glutathione peroxidase 1 (GPX1) but not the classic ferroptosis-inhibiting selenoenzyme GPX4. Selenium-mediated protection from ascorbate was powered by NADPH from the pentose phosphate pathway. In vivo, dietary selenium deficiency resulted in significant enhancement of ascorbate activity against glioblastoma xenografts. These data establish selenoproteins as key mediators of cancer redox homeostasis. Cancer sensitivity to free radical-inducing therapies, including ascorbate, may depend on selenium, providing a dietary approach for improving their anticancer efficacy.
AB - High-dose ascorbate (vitamin C) has shown promising anticancer activity. Two redox mechanisms have been proposed: hydrogen peroxide generation by ascorbate itself or glutathione depletion by dehydroascorbate (formed by ascorbate oxidation). Here we show that the metabolic effects and cytotoxicity of high-dose ascorbate in vitro result from hydrogen peroxide independently of dehydroascorbate. These effects were suppressed by selenium through antioxidant selenoenzymes including glutathione peroxidase 1 (GPX1) but not the classic ferroptosis-inhibiting selenoenzyme GPX4. Selenium-mediated protection from ascorbate was powered by NADPH from the pentose phosphate pathway. In vivo, dietary selenium deficiency resulted in significant enhancement of ascorbate activity against glioblastoma xenografts. These data establish selenoproteins as key mediators of cancer redox homeostasis. Cancer sensitivity to free radical-inducing therapies, including ascorbate, may depend on selenium, providing a dietary approach for improving their anticancer efficacy.
UR - http://www.scopus.com/inward/record.url?scp=85139571630&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139571630&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-22-0408
DO - 10.1158/0008-5472.CAN-22-0408
M3 - Article
C2 - 35916672
AN - SCOPUS:85139571630
SN - 0008-5472
VL - 82
SP - 3486
EP - 3498
JO - Cancer Research
JF - Cancer Research
IS - 19
ER -