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 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 pazopanibmediated 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. K E Y W O R D S apoptosis, endoplasmic reticulum stress (ER-stress), Pazopanib, reactive oxygen species (ROS), small cell lung cancer (SCLC)

Anti-Anaplastic Thyroid Cancer (ATC) Effects and Mechanisms of PLX3397 (Pexidartinib), a Multi-Targeted Tyrosine Kinase Inhibitor (TKI)

“…A widely documented series of small molecule drugs and chemotherapeutic agents induce elevation of ROS and ER stress in cancer cells, including bortezomib, sorafenib, as well as pazopanib, etc. [25,[34][35][36]. As there is no known effective target for pexidartinib in ATC cells, we hypothesize that pexidartinib achieves its antitumor effects by mediating excessive oxidative stress and ER stress.…”

NCI 159456 PERK Inhibitor as a Targeted Therapy for Lung Cancer: An In Vitro Study

“…On the other hand, pazopanib, a multitargeted tyrosine kinase inhibitor, which is known to induce ROS-mediated ER stress and apoptosis in lung cancer, was evaluated in a phase III trial as a maintenance therapy after standard first-line platinum-based chemotherapy in patients with advanced NSCLC [40]. However, this study was stopped because of a lack of efficacy based on strict progression-free survival (PFS) criteria at a futility interim analysis [41].…”

Activation of endoplasmic reticulum stress by harmine suppresses the growth of esophageal squamous cell carcinoma

“…The lack of toxicity of harmine in KYSE‐30 and EC‐9706 cells in our study is a limitation. Lots of studies have shown that anti‐cancer agents can trigger cell apoptosis via reactive oxygen species (ROS)‐mediated ER stress (Li et al, 2022; Liu et al, 2018; Yang et al, 2020), implying that ROS is upstream of ER stress. Recently, Sarita et al found that harmine‐induced generation of ROS leads to cell death (Sarkar et al, 2022).…”