Combination of Arsenic trioxide and Apatinib Synergistically Inhibits Small Cell Lung Cancer by Down-Regulating VEGFR2/mTOR and Akt/c-Myc Signaling Pathway via GRB10

Abstract

Background Small cell lung carcinoma (SCLC) is characterized by poor prognosis. High predilection for -metastasis, -proliferation, and absence of newer therapeutic options. Elucidation of newer pathways characterizing the disease may allow development targeted therapies and favorable outcomes. Methods Combinatorial action of arsenic trioxide (ATO) and apatinib (APA) were tested in-vitro and in-vivo. In-vitro models were tested using H446 and H196 SCLC cell lines. The ability of drugs to reduce metastasis, cell proliferation, and migration was assessed. Using bioinformatic analysis, differentially expressed genes were determined. Using gene knock down models and Western blot technique gene regulation was studied. The in-vivo models were used to confirm the resolution of pathognomic features in the presence of the drugs. GRB10 expression levels of human small cell lung cancer tissues and adjacent tissues were detected by IHC. Results In combination, ATO and APA significantly reduced cell proliferation, migration, and metastasis in both cell lines. Cell proliferation was found to be inhibited by activation of Caspase-3, -7 pathway. In the presence of drugs, it was found that growth factor receptor bound protein (GRB)10 was stabilized. The silencing of GRB10 was found to negatively regulate the VEGFR2/Akt/mTOR and Akt/GSK-3β/c-Myc signaling pathway. Absence of metastasis, reduction of tumor volume was seen in-vivo. The immunohistochemical results confirmed that the expression level of GRB10 in adjacent tissues was significantly higher than that in human small cell lung cancer tissues. Conclusions Synergistically, ATO and APA have a more significant impact on inhibiting cell proliferation than each drug independently. ATO and APA mediate its action through the stabilization of GRB10 thus acting as a tumor suppressor. We thus, preliminarily report the impact of GRB10 stability as a target for SCLC treatment.