Pazopanib restricts small cell lung cancer proliferation via reactive oxygen species‐mediated endoplasmic reticulum stress

• Published in: Thoracic cancer Vol. 13; no. 17; pp. 2421 - 2428
• Main Authors: Li, Yue, Chen, Chen, Liu, Hai‐Lin, Li, Chen‐Guang, Zhang, Zhen‐Fa, Wang, Chang‐Li
• Format: Journal Article
• Language: English
• Published: Melbourne John Wiley & Sons Australia, Ltd 01.09.2022; John Wiley & Sons, Inc; Wiley
• Subjects: Antibodies; Apoptosis; Cancer therapies; Cellulose; Chemotherapy; Endoplasmic reticulum; endoplasmic reticulum stress (ER‐stress); Kidney cancer; Kinases; Lung cancer; Medical prognosis; Original; Pazopanib; Proteins; reactive oxygen species (ROS); small cell lung cancer (SCLC); Software; Statistical analysis; Targeted cancer therapy; Tumors; Variance analysis
• ISSN: 1759-7706; 1759-7714
• DOI: 10.1111/1759-7714.14543

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. Administration of pazopanib upregulates ROS, causing endoplasmic reticulum stress, which finally promotes apoptosis in small cell lung cancer cells.