Desferal regulates hCtr1 and transferrin receptor expression through Sp1 and exhibits synergistic cytotoxicity with platinum drugs in oxaliplatin-resistant human cervical cancer cells in vitro and in vivo

// Szu-Jung Chen 1, 2 , Ching-Chuan Kuo 3 , Hsin-Yi Pan 2 , Tsui-Chun Tsou 4 , Szu-Ching Yeh 4 , Jang-Yang Chang 1, 2, 5 1 Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC 2 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan, ROC 3 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan, ROC 4 Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan, ROC 5 Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC Correspondence to: Jang-Yang Chang, email: jychang@nhri.org.tw , z10208083@email.ncku.edu.tw Keywords: oxaliplatin resistance, copper transporter hCtr1, transferrin transporter TfR1, desferal, specificity protein 1 Sp1 Received: April 11, 2016      Accepted: June 13, 2016      Published: June 30, 2016 ABSTRACT The development of resistance to platinum drugs in cancer cells severely reduces the efficacy of these drugs. Thus, the discovery of novel drugs or combined strategies to overcome drug resistance is imperative. In addition to our previous finding that combined D-penicillamine with platinum drugs exerts synergistic cytotoxicity, we recently identified a novel therapeutic strategy by combining an iron chelating agent desferal with platinum drugs to overcome platinum resistance in an oxaliplatin-resistant human cervical cancer cell line, S3. Further study demonstrated that the level of platinum–DNA adduct formation positively correlated with cell death in combination of desferal with platinums than that of each drug alone in S3 cells. Decrement of human copper transporter 1 (hCtr1) and transferrin receptor 1 (TfR1) expression involved in the development of platinum resistance in S3 cells. Moreover, desferal promoted the expression of hCtr1 through the upregulation of Sp1. The overexpression of Sp1 increased the expression of NF-κB and translocated it into the nucleus to bind to the TfR1 promoter region, which subsequently increased the expression of TfR1. Importantly, the cotreatment of oxaliplatin with desferal significantly potentiated the oxaliplatin-elicited antitumoral effect in the oxaliplatin-resistant xenograft animal model without any toxic effect observed. Taken together, these results demonstrated that the combination of desferal with oxaliplatin can overcome oxaliplatin resistance through the regulation of hCtr1 and TfR1, and may have beneficial effect for treatment of patient with oxaliplatin-refractory tumors.