Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan.
Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya 663-8501, Hyogo, Japan.
Int J Mol Sci. 2022 Apr 4;23(7):4002. doi: 10.3390/ijms23074002.
The use of molecular-targeted drugs in the treatment of gastric cancer is increasing. However, the variety of molecular-targeted drugs in gastric cancer is still limited, and the development of new molecular-targeted therapies is required. The effect of combining sunitinib (SUN) with pterostilbene (PTE) on the human gastric cancer cell lines TMK1 and MKN74 was examined in in vitro and in vivo. Compared with SUN or PTE treatment alone, cotreatment induced pronounced suppression of cell proliferation, with a marked increase in oxidative stress. SUN was associated with a significant retention of mitochondrial Fe. SUN-treated cells decreased expression of PDZ domain-containing protein 8 (PDZD8). Knockdown of PDZD8 in both cells induced Fe retention, and siPDZD8+PTE markedly suppressed cell proliferation with suppressed oxidative phosphorylation, as did the combination of SUN+PTE. In a nude mouse tumor model, a pronounced antitumor effect was observed with SUN+PTE treatment compared to SUN alone. PDZD8 may be a newly discovered off-target for SUN, and that the combined use of PTE with SUN significantly promotes antitumor activity in gastric cancer cell lines. The combined use of SUN and PTE might be a new molecular-targeted therapy for gastric cancer.
在胃癌的治疗中，越来越多地使用分子靶向药物。然而，胃癌中分子靶向药物的种类仍然有限，需要开发新的分子靶向治疗方法。本研究在体外和体内研究了舒尼替尼（SUN）与紫檀芪（PTE）联合对人胃癌细胞系 TMK1 和 MKN74 的作用。与 SUN 或 PTE 单独治疗相比，联合治疗可显著抑制细胞增殖，并显著增加氧化应激。SUN 与线粒体 Fe 的显著保留有关。SUN 处理的细胞下调 PDZ 结构域蛋白 8（PDZD8）的表达。两种细胞中的 PDZD8 敲低诱导 Fe 保留，siPDZD8+PTE 显著抑制细胞增殖，同时氧化磷酸化受到抑制，SUN+PTE 联合治疗也有类似作用。在裸鼠肿瘤模型中，与 SUN 单独治疗相比，SUN+PTE 治疗可显著抑制肿瘤生长。PDZD8 可能是 SUN 的新发现的脱靶，PTE 与 SUN 联合使用可显著促进胃癌细胞系的抗肿瘤活性。SUN 和 PTE 的联合使用可能是胃癌的一种新的分子靶向治疗方法。
