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
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, Peo...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2014-12-01
|
| Series: | Drug Design, Development and Therapy |
| Online Access: | http://www.dovepress.com/sequential-treatment-with-at-101-enhances-cisplatin-chemosensitivity-i-peer-reviewed-article-DDDT |
| _version_ | 1819030226826428416 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Ren T |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-21T06:26:48Z |
| format | Article |
| id | doaj.art-83903124ef304e69a9b98236194ddf34 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-12-21T06:26:48Z |
| publishDate | 2014-12-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-83903124ef304e69a9b98236194ddf342022-12-21T19:13:06ZengDove Medical PressDrug Design, Development and Therapy1177-88812014-12-012014default2517252919546Sequential 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 pathwayRen TShan JQing YQian CLi QLu GLi MLi CPeng YLuo HZhang SZhang WWang DZhou SFTao 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, apoptosishttp://www.dovepress.com/sequential-treatment-with-at-101-enhances-cisplatin-chemosensitivity-i-peer-reviewed-article-DDDT |
| spellingShingle | 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 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 Drug Design, Development and Therapy |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| url | http://www.dovepress.com/sequential-treatment-with-at-101-enhances-cisplatin-chemosensitivity-i-peer-reviewed-article-DDDT |
| work_keys_str_mv | AT rent sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT shanj sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT qingy sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT qianc sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT liq sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT lug sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT lim sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT lic sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT pengy sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT luoh sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT zhangs sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT zhangw sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT wangd sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway AT zhousf sequentialtreatmentwithat101enhancescisplatinchemosensitivityinhumannonsmallcelllungcancercellsthroughinhibitionofapurinicapyrimidinicendonuclease1activatedil6stat3signalingpathway |