ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer
A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-04-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558616303116 |
| _version_ | 1819025374989778944 |
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| author | Eun Young Kim Ji Ye Jung Arum Kim Yoon Soo Chang Se Kyu Kim |
| author_facet | Eun Young Kim Ji Ye Jung Arum Kim Yoon Soo Chang Se Kyu Kim |
| author_sort | Eun Young Kim |
| collection | DOAJ |
| description | A subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models. The synergism of this combination was evaluated by the Chou-Talalay Combination Index method. In vivo activity was evaluated by micro-CT. In NSCLC cells, there was a time and dose-dependent phosphorylation of SRC-JAK2-STAT3 by cisplatin, followed by increased expression of anti-apoptotic molecules. When the expression of the BCL-2 protein family members was evaluated in clinical samples, BCL-xL was most frequently overexpressed. Dominant negative STAT3 suppressed their expression, suggesting that STAT3 mediates cisplatin mediated overexpression of the anti-apoptotic molecules. ABT-737 displaced BCL-xL from mitochondria and induced oligomerization of BAK. ABT-737 itself showed cytotoxic effects and a combination of ABT-737 with cisplatin showed strong synergistic cytotoxicity. In a murine lung cancer model, co-treatment with ABT-737 and cisplatin induced significant tumor regression. These findings reveal a synergistic cytotoxic and anti-tumor activity of ABT-737 and cisplatin co-treatment in preclinical models, and suggest that clinical trials using this strategy may be beneficial in advanced NSCLC. |
| first_indexed | 2024-12-21T05:09:41Z |
| format | Article |
| id | doaj.art-36888c27410943268747080b3374d121 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 |
| language | English |
| last_indexed | 2024-12-21T05:09:41Z |
| publishDate | 2017-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-36888c27410943268747080b3374d1212022-12-21T19:15:05ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862017-04-01194354363ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung CancerEun Young Kim0Ji Ye Jung1Arum Kim2Yoon Soo Chang3Se Kyu Kim4Department of Internal Medicine, 3rd Floor, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Rep of KoreaDepartment of Internal Medicine, 3rd Floor, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Rep of KoreaDepartment of Internal Medicine, 8th Floor Annex Bldg, Gangnam Severance Hospital, Yonsei University College of Medicine, 211-Eonju-ro, Gangnam-gu, 06273, Seoul, Rep of KoreaDepartment of Internal Medicine, 8th Floor Annex Bldg, Gangnam Severance Hospital, Yonsei University College of Medicine, 211-Eonju-ro, Gangnam-gu, 06273, Seoul, Rep of Korea; Address all correspondence to: YS Chang.Department of Internal Medicine, 3rd Floor, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, 03722, Seoul, Rep of KoreaA subset of non-small cell lung cancer (NSCLC), which does not have a druggable driver mutation, is treated with platinum-based cytotoxic chemotherapy, but it develops resistance triggered by DNA damage responses. Here, we investigated the effect of activation of STAT3 by cisplatin on anti-apoptotic proteins and the effectiveness of a co-treatment with cisplatin and a BH3 mimetic, ABT-737. We analyzed the relationship between cisplatin and STAT3 pathway and effect of ABT-737, when combined with cisplatin in NSCLC cells and K-ras mutant mouse models. The synergism of this combination was evaluated by the Chou-Talalay Combination Index method. In vivo activity was evaluated by micro-CT. In NSCLC cells, there was a time and dose-dependent phosphorylation of SRC-JAK2-STAT3 by cisplatin, followed by increased expression of anti-apoptotic molecules. When the expression of the BCL-2 protein family members was evaluated in clinical samples, BCL-xL was most frequently overexpressed. Dominant negative STAT3 suppressed their expression, suggesting that STAT3 mediates cisplatin mediated overexpression of the anti-apoptotic molecules. ABT-737 displaced BCL-xL from mitochondria and induced oligomerization of BAK. ABT-737 itself showed cytotoxic effects and a combination of ABT-737 with cisplatin showed strong synergistic cytotoxicity. In a murine lung cancer model, co-treatment with ABT-737 and cisplatin induced significant tumor regression. These findings reveal a synergistic cytotoxic and anti-tumor activity of ABT-737 and cisplatin co-treatment in preclinical models, and suggest that clinical trials using this strategy may be beneficial in advanced NSCLC.http://www.sciencedirect.com/science/article/pii/S1476558616303116 |
| spellingShingle | Eun Young Kim Ji Ye Jung Arum Kim Yoon Soo Chang Se Kyu Kim ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer Neoplasia: An International Journal for Oncology Research |
| title | ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer |
| title_full | ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer |
| title_fullStr | ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer |
| title_full_unstemmed | ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer |
| title_short | ABT-737 Synergizes with Cisplatin Bypassing Aberration of Apoptotic Pathway in Non-small Cell Lung Cancer |
| title_sort | abt 737 synergizes with cisplatin bypassing aberration of apoptotic pathway in non small cell lung cancer |
| url | http://www.sciencedirect.com/science/article/pii/S1476558616303116 |
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