Gemcitabine in combination with epibrassinolide enhanced the apoptotic response in an ER stress-dependent manner and reduced the epithelial-mesenchymal transition in pancreatic cancer cells

Turkish Journal of Biology · 11 authors, 6 centres

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TL;DR

This preclinical in vitro study examined the combination of gemcitabine and epibrassinolide (EBR) in three pancreatic cancer cell lines with varying genetic characteristics and metastatic potential.

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This preclinical in vitro study examined the combination of gemcitabine and epibrassinolide (EBR) in three pancreatic cancer cell lines with varying genetic characteristics and metastatic potential. The combination of gemcitabine with EBR reduced cell viability, inhibited colony formation, and decreased cell proliferation in a time-dependent manner across all three cell lines. Increased apoptotic cell death was observed following cotreatment, accompanied by cleavage of caspase 9, caspase 3, and PARP, and upregulation of proapoptotic Bax and Bak with downregulation of antiapoptotic Bcl-2. ER stress biomarkers were augmented in a dose-dependent manner, and EBR induced ROS generation. AsPC-1 cells exhibited a more drug-resistant profile than the other cell lines.

STUDY TYPE

other

SPECIALTY

oncology

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ORIGINAL PAPER

PMC10387961

Gemcitabine in combination with epibrassinolide enhanced the apoptotic response in an ER stress-dependent manner and reduced the epithelial-mesenchymal transition in pancreatic cancer cells

Turkish Journal of Biology

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ABSTRACT

Abstract 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. Keywords: Pancreatic cancer, endoplasmic reticulum stress, epibrassinolide, gemcitabine

CITATION EXPORT

Pınar OBAKAN YERLİKAYA, Leila MEHDIZADEHTAPEH, Özge RENCÜZOĞULLARI et al.. Gemcitabine in combination with epibrassinolide enhanced the apoptotic response in an ER stress-dependent manner and reduced the epithelial-mesenchymal transition in pancreatic cancer cells. Turkish Journal of Biology. (2022). https://doi.org/10.55730/1300-0152.2630

AUTHORS

11 · 6 CENTRES

Pınar OBAKAN YERLİKAYA, Leila MEHDIZADEHTAPEH, Özge RENCÜZOĞULLARI, Fadina KURYAYEVA, Sena Sedef ÇEVİKLİ, Şevval ÖZAĞAR, Sibel Pınar ODABAŞ, Sude TUNÇKOL, Hakan YETİM, Ajda ÇOKER GÜRKAN, Elif Damla ARISAN

1Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, İstanbul Medeniyet University, İstanbul, Turkey
2Science and Advanced Technology Research Center, İstanbul Medeniyet University, İstanbul, Turkey
3Department of Food and Nutrition, İstanbul Sabahattin Zaim University, İstanbul, Turkey
4Department of Molecular Biology Genetics, İstanbul Kültür University, İstanbul, Turkey
5Department of Biology, Faculty of Science and Literature, Marmara University, İstanbul, Turkey
6Institute of Biotechnology, Gebze Technical University, Kocaeli, Turkey