单独使用或联合使用三氟尿苷与隐丹参酮抑制胃癌恶性生物学行为的作用及其机制。

Effects and mechanisms of trifluridine alone or in combination with cryptotanshinone in inhibiting malignant biological behavior of gastric cancer.

机构信息

Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.

Department of Hepatobiliary Surgery, Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Hefei, Anhui, China.

出版信息

Cell Cycle. 2023 Jun;22(12):1463-1477. doi: 10.1080/15384101.2023.2215678. Epub 2023 Jun 4.

DOI:10.1080/15384101.2023.2215678

PMID:37272203

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10281482/

Abstract

BACKGROUND

The incidence of gastric cancer (GC) ranks fourth among all malignant tumors worldwide, and the fatality rate ranks second among all malignant tumors. Several Chinese traditional medicines have been used in the treatment of advanced gastric cancer. This study aims to investigate the effect of combinational use of natural product cryptotanshinone (CTS) with anti-cancer drug trifluorothymidine (FTD) in GC.

METHODS

Cell Counting Kit-8 assay was used to detect the inhibitory effect of the combinational or separate use of FTD and CTS on the growth of HGC-27 and AGS GC cells. The combined index of FTD and CTS was calculated using CompuSyn software. To understand the mechanism, we applied flow cytometry to study the cell cycle and cell apoptosis after treatment. We also investigated the amount of FTD incorporated into the DNA by immunofluorescence assay. The expression of relevant proteins was monitored using western blot. Furthermore, the effect of using TAS-102 in combination with CTS was studied in xenograft tumor nude mice model.

RESULTS

FTD and CTS inhibited the growth of GC cells in a dose-dependent manner, respectively. They both exhibited low to sub-micromolar potency in HGC-27 and AGS cells. The combination of FTD and CTS showed synergistic anticancer effect in HGC-27 cells and AGS cells. Our mechanism studies indicate that FTD could block HGC-27 cells at G2/M phase, while CTS could block HGC-27 cells at G1/G0 phase, while FTD combined with CTS could mainly block HGC-27 cells at G2 phase. FTD in combination with CTS significantly increased the apoptosis of HGC-27 cells. We observed that CTS treatment increased the incorporation of FTD into the DNA HGC-27 cell. FTD treatment activated STAT3 phosphorylation in HGC-27 cells, while CTS treatment down-regulated the concentration of p-STAT3. Interestingly, the combination of CTS and FTD reduced STAT3 phosphorylation induced by FTD. In the experiments, we observed that the combination of TAS-102 with CTS was significantly more potent than TAS-102 on tumor growth inhibition.

CONCLUSIONS

FTD combined with CTS has a synergistic anti-gastric cancer effect as shown by and experiments, and the combined treatment of FTD and CTS will be a promising treatment option for advanced gastric cancer.

摘要

背景

胃癌（GC）的发病率在全球所有恶性肿瘤中排名第四，死亡率在所有恶性肿瘤中排名第二。几种中药已被用于治疗晚期胃癌。本研究旨在探讨天然产物隐丹参酮（CTS）与抗癌药物三氟胸苷（FTD）联合应用对 GC 的治疗效果。

方法

使用细胞计数试剂盒-8 检测 FTD 和 CTS 联合或单独使用对 HGC-27 和 AGS GC 细胞生长的抑制作用。使用 CompuSyn 软件计算 FTD 和 CTS 的联合指数。通过流式细胞术研究治疗后细胞周期和细胞凋亡，了解作用机制。我们还通过免疫荧光法检测 FTD 掺入 DNA 的量。使用 Western blot 监测相关蛋白的表达。此外，还在异种移植肿瘤裸鼠模型中研究了 TAS-102 联合 CTS 的效果。

结果

FTD 和 CTS 分别以剂量依赖的方式抑制 GC 细胞生长，在 HGC-27 和 AGS 细胞中均表现出低至亚微摩尔的效力。FTD 和 CTS 联合在 HGC-27 细胞和 AGS 细胞中表现出协同抗癌作用。我们的机制研究表明，FTD 可将 HGC-27 细胞阻滞在 G2/M 期，而 CTS 可将 HGC-27 细胞阻滞在 G1/G0 期，而 FTD 联合 CTS 可主要将 HGC-27 细胞阻滞在 G2 期。FTD 联合 CTS 可显著增加 HGC-27 细胞的凋亡。我们观察到 CTS 处理增加了 FTD 掺入 HGC-27 细胞的 DNA。FTD 处理激活了 HGC-27 细胞中 STAT3 的磷酸化，而 CTS 处理下调了 p-STAT3 的浓度。有趣的是，CTS 和 FTD 的联合减少了 FTD 诱导的 STAT3 磷酸化。在实验中，我们观察到 TAS-102 联合 CTS 对肿瘤生长抑制的作用明显强于 TAS-102。