title: Sequential treatment with AT-101 enhances cisplatin chemosensitivity in human non-small cell lung cancer cells through inhibition of apurinic/apyrimidinic endonuclease 1-activated IL-6/STAT3 signaling pathway.
abstract: AT-101, known as R-(-)-gossypol, is a potent anticancer agent, but its chemosensitizing effects remain elusive. The present study aimed to examine whether AT-101 could increase the sensitivity of non-small cell lung cancer A549 cells to cisplatin (CDDP) and the underlying mechanisms. We evaluated the efficacy of the sequential treatment with AT-101 and CDDP using both in vitro and in vivo models. Our results showed that as compared to AT-101 or CDDP monotherapy, or AT-101 plus CDDP concurrent treatment, the sequential treatment significantly inhibited cell proliferation and migration and induced tumor cell death. Moreover, the efficacy of the sequential treatment was also confirmed in a mouse A549 xenograft model. Our study revealed that AT-101 inhibited the reduced status of apurinic/apyrimidinic endonuclease 1 (APE1) and attenuated APE1-mediated IL-6/STAT3 signaling activation by decreasing IL-6 protein expression; suppressing the STAT3-DNA binding; and reducing the expression of the downstream antiapoptotic proteins Bcl-2 and Bcl-xL. In conclusion, AT-101 enhances the sensitivity of A549 cells to CDDP in vitro and in vivo through the inhibition of APE1-mediated IL-6/STAT3 signaling activation, providing a rationale for the combined use of AT-101 and CDDP in non-small cell lung cancer chemotherapy.
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China ; Oncology Department, The Affiliated Hospital, North Sichuan Medical College, Nanchong, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Ren
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Jinlu
authors.initials: J
authors.lastname: Shan
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qing
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Qian
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Guoshou
authors.initials: G
authors.lastname: Lu
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Mengxia
authors.initials: M
authors.lastname: Li
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Chongyi
authors.initials: C
authors.lastname: Li
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Luo
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Shiheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Zhou
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006072:Gossypol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D015394:Molecular Structure; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D006072:Gossypol; D002945:Cisplatin; C028178:gossypol acetic acid
keywords: APE1; AT101; NSCLC; STAT3; apoptosis; chemosensitivity; cisplatin; nude mice