scholarly journals Possible Role of Cytochrome P450 1B1 in the Mechanism of Gemcitabine Resistance in Pancreatic Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1396
Author(s):  
Erica Yada ◽  
Rika Kasajima ◽  
Atsushi Niida ◽  
Seiya Imoto ◽  
Satoru Miyano ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cytochrome P450 ◽  
Treated Patient ◽  
Gene Set Enrichment Analysis ◽  
Cancer Drug ◽  
Dependent Manner ◽  
Cytochrome P450 1B1 ◽  
Gemcitabine Resistance ◽  
Patient Derived Xenograft ◽  
Xenograft Models

Patient-derived xenograft models reportedly represent original tumor morphology and gene mutation profiles. In addition, patient-derived xenografts are expected to recapitulate the parental tumor drug responses. In this study, we analyzed the pathways involved in gemcitabine resistance using patient-derived xenograft models of pancreatic cancer. The patient-derived xenograft models were established using samples from patients with pancreatic cancer. The models were treated with gemcitabine to better understand the mechanism of resistance to this anti-cancer drug. We performed comparative gene analysis through the next-generation sequencing of tumor tissues from gemcitabine-treated or non-treated patient-derived xenograft mice and gene set enrichment analysis to analyze mRNA profiling data. Pathway analysis of gemcitabine-treated patient-derived xenografts disclosed the upregulation of multiple gene sets and identified several specific gene pathways that could potentially be related to gemcitabine resistance in pancreatic cancer. Further, we conducted an in vitro analysis to validate these results. The mRNA expression of cytochrome P450 1B1 and cytochrome P450 2A6 was upregulated in a concentration-dependent manner following gemcitabine treatment. Moreover, the sensitivity to gemcitabine increased, and viable cells were decreased by the cytochrome P450 1B1 inhibitor, indicating that the cytochrome P450 1B1 pathway may be related to gemcitabine resistance in pancreatic cancer.

scholarly journals Integrative genomic analysis of gemcitabine resistance in pancreatic cancer by patient-derived xenograft models

2021 ◽  
pp. clincanres.3975.2019
Author(s):  
Gang Yang ◽  
Wenfang Guan ◽  
Zhe Cao ◽  
Wenbo Guo ◽  
Guangbing Xiong ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Genomic Analysis ◽  
Gemcitabine Resistance ◽  
Patient Derived Xenograft ◽  
Xenograft Models

scholarly journals Translational pancreatic cancer research: A comparative study on patient-derived xenograft models

2018 ◽  
Vol 24 (7) ◽  
pp. 794-809 ◽  
Author(s):  
Mercedes Rubio-Manzanares Dorado ◽  
Luis Miguel Marín Gómez ◽  
Daniel Aparicio Sánchez ◽  
Sheila Pereira Arenas ◽  
Juan Manuel Praena-Fernández ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Research ◽  
Comparative Study ◽  
Patient Derived Xenograft ◽  
Xenograft Models

scholarly journals Evaluation of TAK-264, an Antibody-Drug Conjugate in Pancreatic Cancer Cell Lines and Patient-Derived Xenograft Models

2018 ◽  
Vol 5 (1) ◽  
pp. 42-49 ◽  
Author(s):  
Anna R. Schreiber ◽  
Anna Nguyen ◽  
Stacey M. Bagby ◽  
John J. Arcaroli ◽  
Betelehem W. Yacob ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Patient Derived Xenograft ◽  
Xenograft Models ◽  
Antibody Drug

scholarly journals ROCK2 Confers Acquired Gemcitabine Resistance in Pancreatic Cancer Cells by Upregulating Transcription Factor ZEB1

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1881 ◽  
Author(s):  
Yang Zhou ◽  
Yunjiang Zhou ◽  
Keke Wang ◽  
Tao Li ◽  
Minda Zhang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Transcriptional Activation ◽  
Coiled Coil ◽  
Ductal Adenocarcinoma ◽  
Dependent Manner ◽  
Promoter Regions ◽  
Gemcitabine Resistance ◽  
Pancreatic Cancer Cells ◽  
Or Gene

Resistance to chemotherapy is a major clinical challenge in the treatment of pancreatic ductal adenocarcinoma (PDAC). Here, we provide evidence that Rho associated coiled-coil containing protein kinase 2 (ROCK2) maintains gemcitabine resistance in gemcitabine resistant pancreatic cancer cells (GR cells). Pharmacological inhibition or gene silencing of ROCK2 markedly sensitized GR cells to gemcitabine by suppressing the expression of zinc-finger-enhancer binding protein 1 (ZEB1). Mechanically, ROCK2-induced sp1 phosphorylation at Thr-453 enhanced the ability of sp1 binding to ZEB1 promoter regions in a p38-dependent manner. Moreover, transcriptional activation of ZEB1 facilitated GR cells to repair gemcitabine-mediated DNA damage via ATM/p-CHK1 signaling pathway. Our findings demonstrate the essential role of ROCK2 in EMT-induced gemcitabine resistance in pancreatic cancer cells and provide strong evidence for the clinical application of fasudil, a ROCK2 inhibitor, in gemcitabine-refractory PDAC.

Preclinical antitumor activity of nanoliposomal irinotecan (Nal-IRI, MM-398) and utilization as a foundation of front-line pancreatic cancer regimens.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 336-336
Author(s):  
Daniel F. Gaddy ◽  
Helen Lee ◽  
Nancy Paz ◽  
Shannon C. Leonard ◽  
Ashish Kalra ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cell Line ◽  
Pancreatic Cancer Cell Line ◽  
Ductal Adenocarcinoma ◽  
Tumor Growth Inhibition ◽  
First Line ◽  
Patient Derived Xenograft ◽  
Nanoliposomal Irinotecan ◽  
Xenograft Models ◽  
Anti Tumor Activity

336 Background: Nanoliposomal irinotecan (nal-IRI, MM-398) recently gained approval in combination with 5-fluorouracil/leucovorin (5-FU/LV) in post-gemcitabine metastatic pancreatic ductal adenocarcinoma (PDAC) based on the extended survival and manageable safety profile observed in the Phase 3 NAPOLI-1 trial. Preclinically, we have previously demonstrated the anti-tumor activity of nal-IRI with 5-FU and oxaliplatin, standard of care agents in first-line PDAC, and are currently investigating this combination in patients with previously untreated metastatic PDAC in a Phase 2 clinical trial (NCT02551991). Herein, we further evaluate nal-IRI as a potential backbone of first-line metastatic PDAC by assessing the preclinical anti-tumor activity of nal-IRI relative to, and in combination with, gemcitabine and nanoparticle albumin-bound-paclitaxel (nab-P). Methods: Nal-IRI tumor metabolite (CPT-11 and SN-38) levels were measured in mice treated with nal-IRI in combination with gemcitabine or nab-P. Anti-tumor activity and tolerability of nal-IRI, 5-FU, gemcitabine and nab-P monotherapies and combinations were evaluated using pancreatic cancer cell line (ASPC-1 and CFPAC-1)-derived xenograft models, as well as a panel of five patient-derived xenograft models. Results: Administration of gemcitabine or nab-P prior to or simultaneously with nal-IRI resulted in unchanged or increased nal-IRI deposition, as measured by tumor CPT-11 and SN-38 levels at 24 hours post-injection. Moreover, in both cell line-derived and patient-derived xenograft models of PDAC, nal-IRI monotherapy demonstrated comparable or improved anti-tumor activity relative to gemcitabine or nab-P monotherapies. Further, nal-IRI consistently improved tumor growth inhibition and survival when used in combination with either 5-FU, gemcitabine and/or nab-P, relative to the combination of gemcitabine plus nab-P. All treatments were well-tolerated in these preclinical models. Conclusions: These findings illustrate the compatibility and therapeutic potential of nal-IRI as a foundation of first-line PDAC combination regimens, and warrant clinical evaluation.

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