Reduced chemotherapeutic sensitivity in high glucose condition: implication of antioxidant response.

// Alessia Garufi 1 , 2 , * , Gianandrea Traversi 1 , 2 , * , Maria Saveria Gilardini Montani 3 , Valerio D’Orazi 4 , Giuseppa Pistritto 5 , Mara Cirone 3 and Gabriella D’Orazi 1 , 2 1 IRCCS Regina Elena National Cancer Institute, Department of Research, Rome 00144, Italy 2 University ‘G. d’Annunzio’, Department of Medical and Biotechnological Sciences, Chieti 66013, Italy 3 Sapienza University, Department of Experimental Medicine, Rome 00161, Italy 4 Department of Surgical Sciences, Rome 00161, Italy 5 University Tor Vergata, Department of Systems Medicine, Rome 00133, Italy * These authors contributed equally to this work Correspondence to: Gabriella D’Orazi, email: gdorazi@unich.it Keywords: chemoresistance; reactive oxygen species (ROS); high glucose (HG); cancer; nuclear factor erythroid 2-related factor 2 (NRF2) Received: April 23, 2019     Accepted: July 05, 2019     Published: July 23, 2019 ABSTRACT Resistance to chemotherapy represents a major obstacle to successful treatment. The generation of reactive oxygen species (ROS) has been directly linked to the cytotoxic effects of several antitumor agents, including Adriamycin (ADR), and modulation of the oxidative balance has been implicated in the development and/or regulation of resistance to chemotherapeutic drugs. We recently showed that high glucose (HG) markedly diminished the cancer cell death induced by anticancer agents such as ADR. In the present study we attempted to evaluate the mechanism that impaired the cytotoxic effect of ADR in HG. We found that, in colon cancer cells, HG attenuated ADR-induced ROS production that consequently diminished ADR-induced H2AX phosphorylation and micronuclei (MN) formation. Mechanistically, HG attenuation of ADR-induced ROS production correlated with increased antioxidant response promoted by NRF2 activity. Thus, pharmacologic inhibition of NRF2 pathway by brusatol re-established the ADR cytotoxic effect impaired by HG. Together, the data provide new insights into chemotherapeutic-resistance mechanisms in HG condition dictated by increased NRF2-induced antioxidant response and how they may be overcome in order to restore chemosensitivity and ADR-induced cell death.