Obakan Yerlikaya Pınar, Mehdizadehtapeh Leila, Rencüzoğullari Özge, Kuryayeva Fadina, Çevikli Sena Sedef, Özağar Şevval, Odabaş Sibel Pınar, Tunçkol Sude, Yetim Hakan, Çoker Gürkan Ajda, Arisan Elif Damla
Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, İstanbul Medeniyet University, İstanbul, Turkey.
Science and Advanced Technology Research Center, İstanbul Medeniyet University, İstanbul, Turkey.
Turk J Biol. 2022 Sep 19;46(6):439-457. doi: 10.55730/1300-0152.2630. eCollection 2022.
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.
吉西他滨是一种广谱抗代谢物，是一种脱氧胞苷类似物，被认为是胰腺癌治疗中单独使用或与其他抗肿瘤药物联合使用的标准疗法。吉西他滨治疗后出现耐药是一种常见现象；因此，联合治疗模式通常更受青睐。胰腺导管腺癌，即胰腺癌，是全球癌症相关死亡的第四大主要原因。随着胰腺癌发病率逐年上升，由于诊断较晚且化疗选择有限，死亡率也显著上升。手术切除后的辅助化疗是早期胰腺癌治疗的典型选择。大多数情况下，5-氟尿嘧啶/亚叶酸与伊立替康和奥沙利铂（FOLFIRINOX）以及吉西他滨/纳米白蛋白结合型紫杉醇用于晚期胰腺癌的预后；然而，通常会出现化疗耐药，限制了化疗的效果。因此，大多数研究都集中在吉西他滨与其他药物联合使用以克服这种情况。作为一种凋亡剂和油菜素内酯的成员，表油菜素内酯（EBR）在不同癌细胞中诱导内质网（ER）应激依赖性细胞死亡，正如我们团队所展示的那样。在本研究中，我们旨在通过EBR联合治疗增强吉西他滨在胰腺癌细胞中的凋亡作用。EBR处理降低了PANC-1、MIA PaCa-2和AsPC-1细胞的细胞活力并抑制了细胞增殖。由于侵袭性不同，每种胰腺癌细胞对EBR处理的反应不同。然而，EBR通过增加活性氧生成诱导凋亡，这与PANC-1和MIA PaCa-2细胞中的内质网应激有关。单独使用吉西他滨降低了每种胰腺癌细胞系的细胞活力；然而，与EBR联合使用导致每种胰腺癌细胞系中凋亡性细胞死亡的进一步诱导。此外，吉西他滨和EBR的联合处理进一步降低了N-钙黏蛋白和波形蛋白的表达，表明胰腺细胞的上皮-间质转化减少。总之，EBR在胰腺癌治疗期间具有避免吉西他滨诱导的副作用的治疗潜力。
