Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.
Anticancer Res. 2022 Jun;42(6):2875-2882. doi: 10.21873/anticanres.15769.
BACKGROUND/AIM: Murine double minute 2 (MDM2) is well known to inhibit p53 function and its over-expression is associated with poor prognosis in several human malignancies. Nutlin-3, a small-molecule inhibitor of MDM2, exerts antitumor effects on various solid tumors harboring wild-type p53. We aimed to clarify its effects on esophageal cancer.
We first examined the potential antitumor effects of nutlin-3 according to MDM2 status using esophageal carcinoma cell lines (KYSE 170/180). We then immunolocalized MDM2 immunoreactivity in 62 surgical cases of esophageal squamous cell carcinoma undergoing neoadjuvant chemotherapy followed by esophagectomy and correlated the findings with clinicopathological variables.
MDM2 mRNA expression in KYSE 170 was significantly higher than that in KYSE 180 cells. No significant changes were detected in both cell lines when nutlin-3 was added. However, cell proliferation was significantly decreased in KYSE 170 cells treated with nutlin-3 and cisplatin compared to cisplatin alone but not in KYSE 180. MDM2 immunoreactivity was also significantly associated with poor sensitivity to neoadjuvant chemotherapy in the cases examined.
The combination of nutlin-3 with chemotherapeutic agents may become a novel therapeutic strategy in esophageal cancer over-expressing MDM2.
背景/目的：鼠双微体 2（MDM2）众所周知可抑制 p53 功能，其过表达与多种人类恶性肿瘤的不良预后相关。MDM2 的小分子抑制剂 Nutlin-3 对携带野生型 p53 的各种实体瘤具有抗肿瘤作用。我们旨在阐明其对食管癌的影响。
我们首先根据食管癌细胞系（KYSE 170/180）中 MDM2 的状态来检查 Nutlin-3 的潜在抗肿瘤作用。然后，我们对接受新辅助化疗后行食管切除术的 62 例食管鳞状细胞癌手术病例进行 MDM2 免疫组化定位，并将这些发现与临床病理变量相关联。
KYSE 170 中的 MDM2 mRNA 表达明显高于 KYSE 180 细胞。添加 Nutlin-3 后，这两种细胞系均未检测到明显变化。然而，与单独使用顺铂相比，用 Nutlin-3 和顺铂处理的 KYSE 170 细胞的细胞增殖明显降低，但在 KYSE 180 细胞中没有。在检查的病例中，MDM2 免疫组化还与新辅助化疗的敏感性差显著相关。
Nutlin-3 与化疗药物的联合可能成为过表达 MDM2 的食管癌的一种新的治疗策略。
