MnTE-2-PyP, a manganese porphyrin, reduces cytotoxicity caused by irradiation in a diabetic environment through the induction of endogenous antioxidant defenses

Arpita Chatterjee, Elizabeth A. Kosmacek, Shashank Shrishrimal, J. Tyson McDonald, Rebecca E. Oberley-Deegan

Research output: Contribution to journalArticle

Abstract

Radiation is a common anticancer therapy for many cancer patients, including prostate cancer. Diabetic prostate cancer patients suffer from increased lymph node metastasis, tumor recurrence and decreased survival as compared to non-diabetic prostate cancer patients. These patients are also at increased risk for enhanced radiation-induced normal tissue damage such as proctitis. Diabetics are oxidatively stressed and radiation causes additional oxidative damage. We and others have reported that, MnTE-2-PyP, a manganese porphyrin, protects normal prostate tissue from radiation damage. We have also reported that, in an in vivo mouse model of prostate cancer, MnTE-2-PyP decreases tumor volume and increases survival of the mice. In addition, MnTE-2-PyP has also been shown to reduce blood glucose and inhibits pro-fibrotic signaling in a diabetic model. Therefore, to investigate the role of MnTE-2-PyP in normal tissue protection in an irradiated diabetic environment, we have treated human prostate fibroblast cells with MnTE-2-PyP in an irradiated hyperglycemic environment. This study revealed that hyperglycemia causes increased cell death after radiation as compared to normo-glycemia. MnTE-2-PyP protects against hyperglycemia-induced cell death after radiation. MnTE-2-PyP decreases expression of NOX4 and α-SMA, one of the major oxidative enzymes and pro-fibrotic molecules respectively. MnTE-2-PyP obstructs NF-κB activity by decreasing DNA binding of the p50-p50 homodimer in the irradiated hyperglycemic environment. MnTE-2-PyP increases NRF2 mediated cytoprotection by increasing NRF2 protein expression and DNA binding. Therefore, we are proposing that, MnTE-2-PyP protects fibroblasts from irradiation and hyperglycemia damage by enhancing the NRF2- mediated pathway in diabetic prostate cancer patients, undergoing radiotherapy.

Original languageEnglish (US)
Article number101542
JournalRedox Biology
Volume34
DOIs
StatePublished - Jul 2020

Keywords

  • Diabetes
  • Hyperglycemia
  • Manganese porphyrin
  • NRF2
  • ROS
  • Radiation

ASJC Scopus subject areas

  • Organic Chemistry
  • Clinical Biochemistry

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