Nrf2 activity as a potential biomarker for the pan-epigenetic anticancer agent, RRx-001
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Shoucheng Ning1, Thillai Veerapazham Sekar2, Jan Scicinski4, Bryan Oronsky4, Donna M. Peehl3, Susan J. Knox1, Ramasamy Paulmurugan2
1Department of Radiation Oncology Stanford University Medical Center Stanford, CA 94305, USA
2Department of Radiology Stanford University Medical Center Stanford, CA 94304, USA
3Department of Urology Stanford University Medical Center Stanford, CA 94305, USA
4EpicentRx, Inc., Mountain View, CA 94041, USA
Ramasamy Paulmurugan, e-mail: [email protected]
Keywords: Nrf2, ARE, biomarker, oxidative stress, cancer
Received: March 23, 2015 Accepted: May 21, 2015 Published: June 04, 2015
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulatory transcription factor that plays an important role in the antioxidant response pathway against anticancer drug-induced cytotoxic effects. RRx-001 is a new anticancer agent that generates reactive oxygen and nitrogen species, and leads to epigenetic alterations in cancer cells. Here we report the RRx-001 mediated nuclear translocation of Nrf2 and the activation of expression of its downstream enzymes HO-1 and NQO1 in tumor cells. Inhibition of intrinsic Nrf2 expression by Nrf2-specific siRNA increased cell sensitivity to RRx-001. Molecular imaging of tumor cells co-expressing pARE-Firefly luciferase and pCMV-Renilla luciferase-mRFP in vitro and in vivo in mice revealed that RRx-001 significantly increased ARE-FLUC signal in cells in a dose- and time-dependent manner, suggesting that RRx-001 is an effective activator of the Nrf2-ARE signaling pathway. The pre-treatment level of ARE-FLUC signal in cells, reflecting basal activity of Nrf2, negatively correlated with the tumor response to RRx-001. The results support the concept that RRx-001 activates Nrf2-ARE antioxidant signaling pathways in tumor cells. Hence measurement of Nrf2-mediated activation of downstream target genes through ARE signaling may constitute a useful molecular biomarker for the early prediction of response to RRx-001 treatment, and thereby guide therapeutic decision-making.
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