Drug Design, Development and Therapy (Dec 2014)

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

  • Ren T,
  • Shan J,
  • Qing Y,
  • Qian C,
  • Li Q,
  • Lu G,
  • Li M,
  • Li C,
  • Peng Y,
  • Luo H,
  • Zhang S,
  • Zhang W,
  • Wang D,
  • Zhou SF

Journal volume & issue
Vol. 2014, no. default
pp. 2517 – 2529

Abstract

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Tao Ren,1,2,* Jinlu Shan,1,* Yi Qing,1 Chengyuan Qian,1 Qing Li,1 Guoshou Lu,1 Mengxia Li,1 Chongyi Li,1 Yu Peng,1 Hao Luo,1 Shiheng Zhang,1 Weiwei Zhang,1 Dong Wang,1 Shu-Feng Zhou3 1Cancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People’s Republic of China; 2Oncology Department, The Affiliated Hospital, North Sichuan Medical College, Nanchong, People’s Republic of China; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA *These authors contributed equally to this work 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. Keywords: AT101, NSCLC, cisplatin, chemosensitivity, APE1, STAT3, nude mice, apoptosis