Background

Pancreatic cancer is one of the most notorious cancers and is known for its highly invasive characteristics, drug resistance, and metastatic progression. Unfortunately, many patients with advanced pancreatic cancer become insensitive towards gemcitabine treatment. Orthosiphon stamineus (O.s) is used widely as a traditional medicine for the treatment of multiple ailments, including cancer in South East Asia. The present in vitro study was designed to investigate the complementary effects of an ethanolic extract of O.s (Et. O.s) or rosmarinic acid in combination with gemcitabine on Panc-1 pancreatic cancer cells.

Method

Cell viability and colony formation assays were used to determine the 50% inhibitory concentration (IC₅₀) of Et. O.s, rosmarinic acid, and gemcitabine. Different doses of gemcitabine in combination with Et. O.s or rosmarinic acid were tested against Panc-1 to select the best concentrations which possessed synergistic effects. Elucidation of molecular mechanisms responsible for mediating chemo-sensitivity in Panc-1 was performed using Quantitative Real-time PCR (QPCR), flow cytometry and immunohistochemistry.

Results

Et. O.s was found to significantly sensitise Panc-1 towards gemcitabine by reducing the gene expression of multidrug-resistant protein family (MDR) (MDR-1, MRP-4, and MRP-5) and molecules related to epithelial-mesenchymal transition (ZEB-1 and Snail-1). An induction of the human equilibrate nucleoside transporter-1 (hENT-1) gene was also found in cells treated with Et. O.s-gemcitabine. The Et. O.s-gemcitabine combination induced cellular senescence, cell death and cell cycle arrest in Panc-1. In addition, the inhibition of Notch signalling was demonstrated through the downregulation of Notch 1 intracellular domain in this treatment group. In contrast, rosmarinic acid-gemcitabine combination showed no additional effects on cellular senescence, apoptosis, epithelial mesenchymal transition (EMT) markers, the MRP-4 and MRP-5 multi-drug resistance protein family, hENT-1, and the Notch pathway through Notch 1 intracellular domain.

Conclusion

This study provides valuable insights on the use of Et. O.s to complement gemcitabine in targeting pancreatic cancer in vitro, suggesting its potential use as a novel complementary treatment in pancreatic cancer patients.

中文翻译：

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Orthosiphon stamineus 标准化乙醇提取物和迷迭香酸联合吉西他滨对胰腺癌的补充作用

背景

胰腺癌是最臭名昭著的癌症之一，以其高度侵袭性、耐药性和转移性进展而闻名。不幸的是，许多晚期胰腺癌患者对吉西他滨治疗变得不敏感。Orthosiphon stamineus ( Os ) 被广泛用作治疗多种疾病的传统药物，包括东南亚的癌症。本体外研究旨在研究Os (Et. Os ) 或迷迭香酸的乙醇提取物与吉西他滨联合对 Panc-1 胰腺癌细胞的互补作用。

方法

细胞活力和集落形成测定用于确定 Et 的 50% 抑制浓度 (IC ₅₀ )。Os、迷迭香酸和吉西他滨。不同剂量的吉西他滨与 Et 组合。Os或迷迭香酸针对Panc-1进行了测试，以选择具有协同作用的最佳浓度。使用定量实时 PCR (QPCR)、流式细胞术和免疫组织化学来阐明负责介导 Panc-1 化学敏感性的分子机制。

结果

等。Os被发现通过降低多药耐药蛋白家族（MDR）（MDR-1、MRP-4和MRP-5）和上皮-间质转化相关分子（ZEB- 1 和蜗牛-1)。在用 Et 处理的细胞中也发现了人类平衡核苷转运蛋白 1 (hENT-1) 基因的诱导。Os-吉西他滨。等。操作系统-吉西他滨组合在Panc-1中诱导细胞衰老、细胞死亡和细胞周期停滞。此外，在该治疗组中通过下调 Notch 1 胞内结构域证明了对 Notch 信号传导的抑制。相比之下，迷迭香酸-吉西他滨组合对细胞衰老、细胞凋亡、上皮间质转化 (EMT) 标志物、MRP-4 和 MRP-5 多药耐药蛋白家族、hENT-1 和 Notch 通路没有额外的影响。 Notch 1 胞内结构域。

结论

这项研究为 Et 的使用提供了宝贵的见解。Os补充吉西他滨在体外靶向胰腺癌中的作用，提示其作为胰腺癌患者新型补充治疗的潜在用途。