Suchergebnisse

Jiangdong Sui,1,2 Mengxia Li,1 Chengyuan Qian,1 Shufeng Wang,3 Yi Cheng,1 Benjamin PC Chen,2 Dong Wang1 1Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China; 2Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3Institute of Immunology, PLA, College of Basic Medical Sciences, Third Military Medical University, Chongqing, People's Republic of China Abstract: Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein possessing both DNA repair and redox regulatory activities. It has been shown that blocking redox function leads to genotoxic, antiangiogenic, cytostatic, and proapoptotic effects in cells. Therefore, the selective inhibitors against APE1's redox function can be served as potential pharmaceutical candidates in cancer therapeutics. In the present study, we identified the biological specificity of the Chinese herbal compound tanshinone IIA (T2A) in blocking the redox function of APE1. Using dual polarization interferometry, the direct interaction between APE1 and T2A was observed with a KD value at subnanomolar level. In addition, we showed that T2A significantly compromised the growth of human cervical cancer and colon cancer cells. Furthermore, the growth-inhibitory or proapoptotic effect of T2A was diminished in APE1 knockdown or redox-deficient cells, suggesting that the cytostatic effect of T2A might be specifically through inhibiting the redox function of APE1. Finally, T2A pretreatment enhanced the cytotoxicity of ionizing radiation or other chemotherapeutic agents in human cervical cancer and colon cancer cell lines. The data presented herein suggest T2A as a promising bioactive inhibitor of APE1 redox activity. Keywords: tanshinone IIA, APE1, redox activity, multifunctional protein

Chengyuan Qian, Mengxia Li, Jiangdong Sui, Tao Ren, Zheng Li, Liang Zhang, Liwei Zhou, Yi Cheng, Dong WangCancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of ChinaAbstract: The human apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (APE1/Ref-1), an essential multifunctional protein involved in the repair of oxidative deoxyribonucleic acid (DNA) damage and transcriptional regulation, is often overexpressed in tumor tissues and cancer cells. Moreover, APE1/Ref-1 (APE1) overexpression has been linked to chemoresistance in human tumors. Thus, inhibiting APE1 function in cancer cells is considered a promising strategy to overcome resistance to therapeutic agents. Gossypol is a Bcl-2 homology 3 (BH3)-mimetic agent and is able to bind to the BH3 domain of B-cell lymphoma 2 (Bcl-2) family members. Other studies demonstrated that Bcl-2 directly interacted with APE1 via its BH domains. Using apurinic/apyrimidinic (AP) endonuclease assays, we found that gossypol inhibits the repair activity of APE1. Electrophoretic mobility shift assays and dual luciferase assays showed that gossypol could also inhibit the redox function of APE1. Using dual polarization interferometry technology, we show that gossypol can directly interact with APE1. Furthermore, addition of gossypol, in conjunction with APE1 overexpression, leads to cancer cell death. The addition of gossypol also enhances the cell killing effect of the laboratory alkylating agent methyl methanesulfonate and the clinical agent cisplatin (DDP). Administration of gossypol significantly inhibited the growth of xenografts. Furthermore, the combined treatment of gossypol and DDP resulted in a statistically higher antitumor activity compared with DDP alone in vivo. In conclusion, we have demonstrated that gossypol effectively inhibits the repair and redox activity of APE1 through a direct interaction.Keywords: cancer, oxidative DNA damage, BH3-mimetic