scholarly journals Brusatol Enhances the Chemotherapy Efficacy of Gemcitabine in Pancreatic Cancer via the Nrf2 Signalling Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yukai Xiang ◽  
Wen Ye ◽  
Chaohao Huang ◽  
Dinglai Yu ◽  
Hao Chen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Advanced Pancreatic Cancer ◽  
Signalling Pathway ◽  
Human Pancreatic Cancer ◽  
Control Treatment ◽  
Nrf2 Pathway ◽  
Pancreatic Cancer Cells ◽  
Nrf2 Activation

Although gemcitabine is the standard chemotherapy treatment for advanced pancreatic cancer, its benefits are quite limited due to prevalent chemoresistance, and the mechanism underlying gemcitabine chemoresistance remains unclear. Currently, Nrf2 has been deemed as a significant contributor to gemcitabine chemoresistance in pancreatic cancer. Brusatol is a unique inhibitor of the Nrf2 pathway, and in previous studies, we determined that brusatol exhibits the effects of growth inhibition and proapoptosis in pancreatic cancer cells. Due to these data, we speculate that brusatol can reverse gemcitabine-induced Nrf2 activation and propose that it can enhance gemcitabine efficacy in treating pancreatic cancer. In this study, we first proved that brusatol can effectively inhibit the Nrf2 signalling pathway and increase ROS accumulation in pancreatic cancer cells. Next, we demonstrated that brusatol can abrogate gemcitabine-induced Nrf2 activation in pancreatic cancer cells. In addition, we discovered that brusatol potentiates gemcitabine-induced growth inhibition and apoptosis in human pancreatic cancer cells. In nude mice with PANC-1 xenografts, treatment with a combination of brusatol and gemcitabine considerably reduced in vivo tumour growth compared with control treatment or treatment with either brusatol or gemcitabine alone. Immunohistochemical staining also showed that Nrf2 expression levels were reduced in brusatol-treated xenograft tumour tissues. In summary, our results suggest that brusatol is capable of enhancing the antitumour effects of gemcitabine in both pancreatic cancer cells and PANC-1 xenografts via suppressing the Nrf2 pathway.

scholarly journals Nrf2 Activation Sensitizes K-Ras Mutant Pancreatic Cancer Cells to Glutaminase Inhibition

2021 ◽  
Vol 22 (4) ◽  
pp. 1870
Author(s):  
Shin Hamada ◽  
Ryotaro Matsumoto ◽  
Yu Tanaka ◽  
Keiko Taguchi ◽  
Masayuki Yamamoto ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Therapeutic Interventions ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancers ◽  
Pancreatic Cancer Cells ◽  
Nrf2 Activation

Pancreatic cancer remains intractable owing to the lack of effective therapy for unresectable cases. Activating mutations of K-ras are frequently found in pancreatic cancers, but these have not yet been targeted by cancer therapies. The Keap1-Nrf2 system plays a crucial role in mediating the oxidative stress response, which also contributes to cancer progression. Nrf2 activation reprograms the metabolic profile to promote the proliferation of cancer cells. A recent report suggested that K-ras- and Nrf2-active lung cancer cells are sensitive to glutamine depletion. This finding led to the recognition of glutaminase inhibitors as novel anticancer agents. In the current study, we used murine pancreatic cancer tissues driven by mutant K-ras and p53 to establish cell lines expressing constitutively activated Nrf2. Genetic or pharmacological Nrf2 activation in cells via Keap1 deletion or Nrf2 activation sensitized cells to glutaminase inhibition. This phenomenon was confirmed to be dependent on K-ras activation in human pancreatic cancer cell lines harboring mutant K-ras, i.e., Panc-1 and MiaPaCa-2 in response to DEM pretreatment. This phenomenon was not observed in BxPC3 cells harboring wildtype K-ras. These results indicate the possibility of employing Nrf2 activation and glutaminase inhibition as novel therapeutic interventions for K-ras mutant pancreatic cancers.

scholarly journals Growth delay of human pancreatic cancer cells by methylase inhibitor 5-aza-2′-deoxycytidine treatment is associated with activation of the interferon signalling pathway

Oncogene ◽  
2005 ◽  
Vol 24 (1) ◽  
pp. 199-211 ◽  
Author(s):  
Edoardo Missiaglia ◽  
Massimo Donadelli ◽  
Marta Palmieri ◽  
Tatjana Crnogorac-Jurcevic ◽  
Aldo Scarpa ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Signalling Pathway ◽  
Human Pancreatic Cancer ◽  
Growth Delay ◽  
Pancreatic Cancer Cells ◽  
Interferon Signalling

Rescuing TGFb-Smad signalling pathway restores growth inhibition by TGFb in pancreatic cancer cells

2000 ◽  
Vol 118 (4) ◽  
pp. A47
Author(s):  
Hideaki Ijichi ◽  
Naoya Kato ◽  
Tsuneo Ikenoue ◽  
Jun Kato ◽  
Makoto Ohashi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Signalling Pathway ◽  
Pancreatic Cancer Cells

scholarly journals Soluble VCAM-1 promotes gemcitabine resistance via macrophage infiltration and predicts therapeutic response in pancreatic cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ryota Takahashi ◽  
Hideaki Ijichi ◽  
Makoto Sano ◽  
Koji Miyabayashi ◽  
Dai Mohri ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Cancer Cells ◽  
Advanced Pancreatic Cancer ◽  
Genetically Engineered ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Genetically Engineered Mouse Model ◽  
Gemcitabine Treatment

AbstractPancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.

KLF8 knockdown triggered growth inhibition and induced cell phase arrest in human pancreatic cancer cells

Gene ◽  
2016 ◽  
Vol 585 (1) ◽  
pp. 22-27 ◽  
Author(s):  
Xiaoping Yi ◽  
Yixiong Li ◽  
Hongyan Zai ◽  
Xueying Long ◽  
Wenzheng Li
Keyword(s):  
Pancreatic Cancer ◽  
Growth Inhibition ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
Phase Arrest
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