Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress
Abstract Background Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti‐SCLC mechanisms of pazopanib...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-09-01
|
| Series: | Thoracic Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1111/1759-7714.14543 |
| _version_ | 1811186788606148608 |
|---|---|
| author | Yue Li Chen Chen Hai‐Lin Liu Chen‐Guang Li Zhen‐Fa Zhang Chang‐Li Wang |
| author_facet | Yue Li Chen Chen Hai‐Lin Liu Chen‐Guang Li Zhen‐Fa Zhang Chang‐Li Wang |
| author_sort | Yue Li |
| collection | DOAJ |
| description | Abstract Background Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti‐SCLC mechanisms of pazopanib remain unclear. Methods Cell viability was evaluated by CCK‐8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic‐related molecules and ER‐stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH‐HA staining followed by flow cytometry. An NCI‐H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI‐H446 cell‐bearing NOD‐SCID mice. Results Pazopanib dose‐ and time‐dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved‐caspase3 and Bax, and decreased Bcl‐2. Moreover, the PERK‐related ER‐stress pathway was potently activated by pazopanib treatment, inhibiting ER‐stress by salubrinal significantly reversing pazopanib‐mediated apoptosis in SCLC cell lines. Furthermore, pazopanib‐induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib‐induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI‐H446 xenograft growth and decreased Ki67 positive cells in the tumor. Conclusion Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER‐stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated. |
| first_indexed | 2024-04-11T13:52:17Z |
| format | Article |
| id | doaj.art-00ce8925deb2498197caf2ddfd0daacb |
| institution | Directory Open Access Journal |
| issn | 1759-7706 1759-7714 |
| language | English |
| last_indexed | 2024-04-11T13:52:17Z |
| publishDate | 2022-09-01 |
| publisher | Wiley |
| record_format | Article |
| series | Thoracic Cancer |
| spelling | doaj.art-00ce8925deb2498197caf2ddfd0daacb2022-12-22T04:20:31ZengWileyThoracic Cancer1759-77061759-77142022-09-0113172421242810.1111/1759-7714.14543Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stressYue Li0Chen Chen1Hai‐Lin Liu2Chen‐Guang Li3Zhen‐Fa Zhang4Chang‐Li Wang5Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center Tianjin ChinaDepartment of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center Tianjin ChinaDepartment of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center Tianjin ChinaDepartment of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center Tianjin ChinaDepartment of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center Tianjin ChinaDepartment of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center Tianjin ChinaAbstract Background Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti‐SCLC mechanisms of pazopanib remain unclear. Methods Cell viability was evaluated by CCK‐8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic‐related molecules and ER‐stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH‐HA staining followed by flow cytometry. An NCI‐H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI‐H446 cell‐bearing NOD‐SCID mice. Results Pazopanib dose‐ and time‐dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved‐caspase3 and Bax, and decreased Bcl‐2. Moreover, the PERK‐related ER‐stress pathway was potently activated by pazopanib treatment, inhibiting ER‐stress by salubrinal significantly reversing pazopanib‐mediated apoptosis in SCLC cell lines. Furthermore, pazopanib‐induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib‐induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI‐H446 xenograft growth and decreased Ki67 positive cells in the tumor. Conclusion Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER‐stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated.https://doi.org/10.1111/1759-7714.14543apoptosisendoplasmic reticulum stress (ER‐stress)Pazopanibreactive oxygen species (ROS)small cell lung cancer (SCLC) |
| spellingShingle | Yue Li Chen Chen Hai‐Lin Liu Chen‐Guang Li Zhen‐Fa Zhang Chang‐Li Wang Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress Thoracic Cancer apoptosis endoplasmic reticulum stress (ER‐stress) Pazopanib reactive oxygen species (ROS) small cell lung cancer (SCLC) |
| title | Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress |
| title_full | Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress |
| title_fullStr | Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress |
| title_full_unstemmed | Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress |
| title_short | Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress |
| title_sort | pazopanib restricts small cell lung cancer proliferation via reactive oxygen species mediated endoplasmic reticulum stress |
| topic | apoptosis endoplasmic reticulum stress (ER‐stress) Pazopanib reactive oxygen species (ROS) small cell lung cancer (SCLC) |
| url | https://doi.org/10.1111/1759-7714.14543 |
| work_keys_str_mv | AT yueli pazopanibrestrictssmallcelllungcancerproliferationviareactiveoxygenspeciesmediatedendoplasmicreticulumstress AT chenchen pazopanibrestrictssmallcelllungcancerproliferationviareactiveoxygenspeciesmediatedendoplasmicreticulumstress AT hailinliu pazopanibrestrictssmallcelllungcancerproliferationviareactiveoxygenspeciesmediatedendoplasmicreticulumstress AT chenguangli pazopanibrestrictssmallcelllungcancerproliferationviareactiveoxygenspeciesmediatedendoplasmicreticulumstress AT zhenfazhang pazopanibrestrictssmallcelllungcancerproliferationviareactiveoxygenspeciesmediatedendoplasmicreticulumstress AT changliwang pazopanibrestrictssmallcelllungcancerproliferationviareactiveoxygenspeciesmediatedendoplasmicreticulumstress |