Harbin Medical University, Harbin, Heilongjiang Province, China.
Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
Hereditas. 2024 Sep 2;161(1):29. doi: 10.1186/s41065-024-00330-2.
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 for development of targeted therapies and consequently favorable outcomes.
The current study explored the combinatorial action of arsenic trioxide (ATO) and apatinib (APA) 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 were assessed. Using bioinformatic analysis, differentially expressed genes were determined. Gene regulation was assessed using gene knock down models and confirmed using Western blots. The in vivo models were used to confirm the resolution of pathognomic features in the presence of the drugs. Growth factor receptor bound protein (GRB) 10 expression levels of human small cell lung cancer tissues and adjacent tissues were detected by IHC.
In combination, ATO and APA were found to significantly reduce -cell proliferation, -migration, and -metastasis in both the 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 expression of GRB10 was stabilized. The silencing of GRB10 was found to negatively regulate the VEGFR2/Akt/mTOR and Akt/GSK-3β/c-Myc signaling pathway. Concurrently, absence of metastasis and reduction of tumor volume were confirmed 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.
Synergistically, ATO and APA have a more significant impact on inhibiting cell proliferation than each drug independently. ATO and APA may be mediating 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.
小细胞肺癌（SCLC）的特点是预后差、易转移、增殖活跃，且治疗选择有限。阐明疾病的新途径可能有助于开发靶向治疗方法，并带来有利的结果。
本研究在体外和体内探索了三氧化二砷（ATO）和阿帕替尼（APA）的联合作用。体外模型使用 H446 和 H196 SCLC 细胞系进行测试。评估药物降低转移、细胞增殖和迁移的能力。使用生物信息学分析确定差异表达基因。使用基因敲低模型评估基因调控，并使用 Western blot 进行验证。体内模型用于确认药物存在时病理特征的缓解。通过免疫组化检测人小细胞肺癌组织和相邻组织中生长因子受体结合蛋白 10（GRB10）的表达水平。
ATO 和 APA 联合使用时，发现它们可显著降低两种细胞系中的细胞增殖、迁移和转移。细胞增殖被发现通过激活 Caspase-3、-7 途径受到抑制。在药物存在的情况下，发现 GRB10 的表达得到稳定。GRB10 的沉默被发现负调控 VEGFR2/Akt/mTOR 和 Akt/GSK-3β/c-Myc 信号通路。同时，体内也证实了转移的减少和肿瘤体积的缩小。免疫组化结果证实，相邻组织中 GRB10 的表达水平明显高于人小细胞肺癌组织。
ATO 和 APA 联合使用对抑制细胞增殖的影响比单独使用每种药物更为显著。ATO 和 APA 可能通过稳定 GRB10 发挥作用，从而作为肿瘤抑制因子。因此，我们初步报告了 GRB10 稳定性作为 SCLC 治疗靶点的影响。
