吉西他滨是一种广谱抗代谢药和脱氧胞苷类似物，已被公认为胰腺癌治疗中的标准疗法，可单独应用或与其他抗肿瘤药物联合使用。吉西他滨治疗后出现耐药现象是常见的；因此，通常更倾向于采取联合治疗方案。胰腺导管腺癌，即胰腺癌，是全球癌症相关死亡的第四大原因。随着每年胰腺癌发病率的增加，由于晚期诊断和有限的化疗选择，死亡率也显著上升。手术切除后的辅助化疗是治疗早期胰腺癌的典型选择。通常用5-氟尿嘧啶/亚叶酸钙联用伊立替康和奥沙利铂（FOLFIRINOX）以及吉西他滨/纳立帕克税尔用于晚期胰腺癌的预后；然而，化疗抗药性通常会限制化疗的有效性。因此，大多数研究都侧重于吉西他滨与其他药物的联合使用以克服这种情况。作为一种细胞凋亡剂和油菜素类激素成员，表外油素（EBR）通过我们小组的研究表明，诱导不同癌细胞中的内质网（ER）应激依赖性细胞死亡。在本研究中，我们旨在通过吉西他滨与EBR联合治疗增强胰腺癌细胞的凋亡效应。EBR处理降低了PANC-1、MIA PaCa-2和AsPC-1细胞的细胞存活率并抑制了细胞增殖。由于侵袭性的不同，每个胰腺癌细胞对EBR的反应不同。然而，EBR通过增加ROS生成诱导了PANC-1和MIA PaCa-2细胞中的细胞凋亡，与ER应激相关。吉西他滨单独减少了每个胰腺癌细胞系的细胞存活率；然而，与EBR联合治疗导致每个胰腺癌细胞系中进一步诱导凋亡细胞死亡。此外，吉西他滨和EBR的联合治疗进一步降低了N-钙黏蛋白和波形蛋白的表达，表明胰腺细胞的上皮间质转化得到减少。总之，EBR在胰腺癌治疗中具有避免吉西他滨引起的副作用的治疗潜力。© TÜBİTAK.

Gemcitabine is a broad-spectrum antimetabolite and a deoxycytidine analog recognized as a standard therapy alone or in combination with other antineoplastic agents in the therapy of pancreas cancer. Drug resistance following gemcitabine treatment is a common phenomenon; therefore, combinational therapy models are usually preferred. Pancreatic ductal adenocarcinoma, or pancreas cancer, is the fourth leading cause of cancer-related deaths worldwide. With the increasing incidence of pancreatic cancer every year, the mortality rate is also rising significantly because of late diagnosis, and limited chemotherapy options. Adjuvant chemotherapy after surgical resection is the typical option for the treatment of early pancreatic cancer. Mostly, 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel is used for the prognosis of advanced pancreatic cancer; however, chemoresistance usually occurs limiting the effectiveness of the chemotherapy. Therefore, most of the studies are focused on gemcitabine combination with other drugs to overcome the situation. As an apoptotic agent and a member of brassinosteroids, epibrassinolide (EBR) induces endoplasmic reticulum (ER) stress-dependent cell death in different cancer cells, as shown by our group. In this study, we aimed to enhance the gemcitabine apoptotic effect by EBR combined treatment in pancreatic cancer cells. EBR treatment reduced cell viability and inhibited cell proliferation in PANC-1, MIA PaCa-2, and AsPC-1 cells. Each pancreatic cancer cell gave different responses to the EBR treatment because of different aggressiveness. However, EBR induced apoptosis through increasing ROS generation, which was associated with ER stress in PANC-1 and MIA PaCa-2 cells. Gemcitabine alone reduced the cell viability of each pancreatic cancer cell line; however, combination with EBR led to further induction of apoptotic cell death in each pancreatic cancer cell line. In addition, combined treatment of gemcitabine and EBR further decreased N-cadherin and vimentin expressions, suggesting that epithelial-mesenchymal transition of pancreatic cells is reduced. In conclusion, EBR had therapeutic potential to avoid the gemcitabine-induced side effects during the treatment of pancreatic cancer.© TÜBİTAK.