Development of 177Lu-DN(C19)-CXCR4 Ligand Nanosystem for Combinatorial Therapy in Pancreatic Cancer

2021 ◽  
Vol 17 (2) ◽  
pp. 263-278
Author(s):  
Maydelid Trujillo-Nolasco ◽  
Pedro Cruz-Nova ◽  
Guillermina Ferro-Flores ◽  
Brenda Gibbens-Bandala ◽  
Enrique Morales-Avila ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Therapeutic Strategy ◽  
Pancreatic Tumors ◽  
Pancreatic Cell ◽  
Pancreatic Cancer Cells ◽  
Cxcr4 Receptor ◽  
Specific Uptake ◽  
Viral Oncogene Homolog

Pancreatic cancer is highly lethal and has a poor prognosis. The most common alteration during the formation of pancreatic tumors is the activation of KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) oncogene. As a new therapeutic strategy, the C19 molecule ((2S)-N-(2,5-dichlorophenyl)-2-[(3,4-dimethoxyphenyl)-methylamine]propanamide) blocks the KRAS-membrane association in cancer cells. In addition, the chemokine receptor CXCR4 is overexpressed in pancreatic cancer. In this research, a new dendrimer-based nanoradiopharmaceutical (177Lu-DN(C19)-CXCR4L) encapsulating C19 and functionalized to target CXCR4 receptors is proposed as both, a targeted radiotherapy system (lutetium-177) and an oncotherapeutic approach by the stabilization of KRAS4b-PDESδ complex to produce dual-specific therapy in pancreatic cancer. 177The Lu-DN(C19)-CXCR4L was synthesized and characterized, C19 was encapsulated with 81% efficiency, the final nanosystem rendered a particle size of 67 nm and the specific uptake in pancreatic cell lines was demonstrated. The major cytotoxic effect was observed in the KRAS-dependent and radioresistant cell line Mia PaCa-2, which expresses a high density of CXCR4 receptors. The radiation dose of 3 Gy/Bq decreased viability to 7%, and this effect was attributed to the presence of C19. A synergistic effect (radio and chemotherapy) capable of reducing viability in pancreatic cancer cells through apoptotic mechanisms was demonstrated. Thus, 177Lu-DN(C19)-CXCR4L nanoradiopharmaceutical is efficacious in pancreatic cancer cell lines overexpressing the CXCR4 receptor.

scholarly journals Metabolic Response of Pancreatic Carcinoma Cells under Treatment with Dichloroacetate

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 350
Author(s):  
Benedikt Feuerecker ◽  
Philipp Biechl ◽  
Christian Veltkamp ◽  
Dieter Saur ◽  
Wolfgang Eisenreich
Keyword(s):  
Pancreatic Cancer ◽  
Amino Acids ◽  
Cancer Cells ◽  
Treatment Response ◽  
Cell Lines ◽  
Metabolic Response ◽  
Gas Chromatography Mass Spectrometry ◽  
Glycolytic Flux ◽  
Pancreatic Cell ◽  
Pancreatic Cancer Cells

In modern oncology, the analysis and evaluation of treatment response are still challenging. Hence, we used a 13C-guided approach to study the impacts of the small molecule dichloroacetate (DCA) upon the metabolic response of pancreatic cancer cells. Two different oncogenic PI3K-driven pancreatic cancer cell lines, 9580 and 10,158, respectively, were treated with 75 mM DCA for 18 h. In the presence of [U-13C6]glucose, the effects of DCA treatment in the core carbon metabolism were analyzed in these cells using gas chromatography–mass spectrometry (GC/MS). 13C-enrichments and isotopologue profiles of key amino acids revealed considerable effects of the DCA treatment upon glucose metabolism. The DCA treatment of the two pancreatic cell lines resulted in a significantly decreased incorporation of [U-13C6]glucose into the amino acids alanine, aspartate, glutamate, glycine, proline and serine in treated, but not in untreated, cancer cells. For both cell lines, the data indicated some activation of pyruvate dehydrogenase with increased carbon flux via the TCA cycle, but also massive inhibition of glycolytic flux and amino acid biosynthesis presumably by inhibition of the PI3K/Akt/mTORC axis. Together, it appears worthwhile to study the early treatment response in DCA-guided or accompanied cancer therapy in more detail, since it could open new avenues for improved diagnosis and therapeutic protocols of cancer.

Novel therapeutic strategy to inhibit growth of pancreatic cancer organoids using a rational combination of drugs to induce mitotic arrest and apoptosis.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 322-322 ◽  
Author(s):  
Zhijian Duan ◽  
Mei-Juan Tu ◽  
Qianyu Zhang ◽  
May Thet Cho ◽  
Jasmine Huynh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Combined Treatment ◽  
Cancer Therapeutics ◽  
Mitotic Arrest ◽  
Pancreatic Cell ◽  
Single Drug ◽  
Pancreatic Cancer Cells ◽  
Bh3 Mimetic

322 Background: The ability of cancer cells to suppress apoptosis is critical for carcinogenesis. The Bcl-2-family of regulator proteins, including the anti-apoptotic members Bcl-2, Bcl-xL and Mcl-1, contributes to a complex network in control of apoptosis. BH3-mimetics (e.g. ABT-263) can inhibit anti-apoptotic Bcl-2 proteins and therefore have been developed as potential cancer therapeutics. Aurora Kinase A (AKA) is over-expressed in pancreatic cancer (PC) and is expressed to regulate G2-M transition during mitosis, making it an attractive target for PC. In this study we hypothesized that a combination of mitotic arrest using an AKA inhibitor (e.g. MLN8237) would sensitize PC to induction of apoptosis by a BH3-mimetic. Methods: Pancreatic cell lines (AsPC-1, PANC-1, MIA PaCa-2, HPAF-II) and patient-derived pancreatic cancer organoids (PDO) were treated with a BH3-mimetic (ABT-263) alone, an AKA inhibitor (MLN8237) alone, or the combination in comparison to untreated controls. Cell viability was measured using the CellTiter-Fluor (Promega) assay. Apoptosis was evaluated by Western blot (WB) for cleaved PARP, caspase 3 or caspase 7, and flow cytometry. Nude mice were implanted with pancreatic cancer cells to generate PC xenografts which were then treated with the same 4 treatment groups as in the in vitro studies. Results: ABT-263 combined with MLN8237 showed greater potency than either single drug alone, demonstrating synergy in inhibiting the growth of PC cells and PDOs. Combined treatment with MLN8237 and ABT-263 in PDOs suppressed organoid formation and proliferation by inducing apoptosis. Mechanistically, MLN8237 enhanced the activity of ABT-263 through reduction of Bcl-xL and Mcl-1 in pancreatic cancer cell lines and PDOs. The combination therapy also showed greater suppression of the growth of xenograft tumors, as compared with control treatments with single drug alone or vehicle. Conclusions: The combination of ABT-263 and MLN8237 appears to synergistically induce apoptosis via reduction of Bcl-2 family proteins in PC and should be further explored.

scholarly journals Anticancer effects of miR-124 delivered by BM-MSC derived exosomes on cell proliferation, epithelial mesenchymal transition, and chemotherapy sensitivity of pancreatic cancer cells

2020 ◽  
Author(s):  
Yan Xu ◽  
Nanbin Liu ◽  
Yuhua Wei ◽  
Deren Zhou ◽  
Rui Lin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Pancreatic Tumors ◽  
Luciferase Reporter ◽  
Protective Effects ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Abstract Objective This study aims to explore the roles of miR-124 in pancreatic tumor and potential vehicles. Methods The expression of miR-124 and EZH2 was determined in both pancreatic cancer tissues and cell lines. miR-124 or EZH2 was overexpressed in AsPC-1 and PANC1 cells. Then, the effects on cell viability. apoptosis, invasion, migration and epithelial mesenchymal transition were evaluated. Afterwards, the roles of miR-124 on the expression and function of EZH2 in pancreatic tumors were determined by dual luciferase reporter assay. Subsequently, miR-124 was transfected to bone marrow mesenchymal stromal cells (BM-MSCs), and the BM-MSCs derived exosomes were isolated and co-cultured with AsPC-1 and PANC1 cells, or injected into pancreatic cancer tumor-bearing mice. Results The miR-124 expression levels decreased in pancreatic adenocarcinoma tissues and cancer cell lines AsPC-1, PANC1, BxPC-3 and SW1990. Furthermore, the elevated expression of miR-124 in AsPC-1 and PANC1 via miR-124 mimic transfection-induced apoptosis, metastasis and epithelial mesenchymal transition was suppressed, and the EZH2 overexpression partly reversed the protective effects of miR-124 against pancreatic tumors. In addition, the expression of miR-124 was detected in exosomes extracted from miR-124-transfected BM-MSCs, and these exosomes delivered miR-124 into pancreatic cancer cells, and presented the anti-tumor effects in vitro and in vivo. Conclusion MiR-124-carried BM-MSC-derived exosomes have potential applications for the treatment of pancreatic tumors.

Reactivation of p53 mutant protein by PRIMA-1 and induction of apoptosis in pancreatic cancer cells.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13546-e13546
Author(s):  
Patricia Izetti ◽  
Agnes Hautefeuille ◽  
Ana Lucia Abujamra ◽  
Caroline Brunetto de Farias ◽  
Rafael Roesler ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
In Vitro Models ◽  
Brdu Incorporation ◽  
Mutant P53 ◽  
Pancreatic Cell ◽  
Pancreatic Cancer Cells ◽  
Induced Apoptosis

e13546 Background: Inactivating TP53 mutations are common events in different types of cancers, including pancreatic adenocarcinoma, where it occurs in as much as 70% of cases. Accumulation of mutant p53 provides a molecular target that may be reactivated into a conformation capable of arresting tumor growth. The small molecule PRIMA-1 (p53 reactivation and induction of massive apoptosis) has been shown to selectively induce apoptosis in tumor cells by reactivating some p53 mutants, but no previous studies have investigated its effects in pancreatic cancer. Methods: PANC-1 (mutant TP53 R273H) and CAPAN-2 (wild-type TP53) pancreatic cell lines were used as in vitro models. We tested the effects of PRIMA-1 on cell viability (MTT assay), apoptosis (morphology, AnnexinV/FITC-FACS), cell cycle (BrdU incorporation) and expression of p53 regulated proteins by western blotting. As control of p53-dependent effects, PANC-1 cell lines were transfected with siRNA against TP53 (sip53). Results: PRIMA-1 selectively induced apoptosis in PANC-1 cells compared to CAPAN-2 cells and this effect was concomitant with an increase in the levels of MDM2, Bax and cleaved caspase-3 as detected by western blot analysis. Treatment with PRIMA-1 for 24h induced a 50% reduction in DNA synthesis whereas G2/M arrest was detected after 12h of treatment. p53 silencing in PANC-1 decreased the cytotoxicity of PRIMA-1, characterizing a p53-dependent effect. Finally, N-acetylcysteine completely blocked PRIMA-1-induced growth suppression and apoptosis, suggesting that PRIMA-1 exerts its effect at least in part via restoring redox-dependent effects to mutant p53. Conclusions: Our data indicate that PRIMA-1 induces apoptosis in TP53 mutant pancreatic cancer cells by promoting the re-activation of p53 and subsequent of proapoptotic signaling pathways, suggesting a possible mechanism for effective targeting of pancreatic cancer.

scholarly journals Anticancer Effects of miR-124 Delivered by BM-MSC Derived Exosomes on Cell Proliferation, Epithelial Mesenchymal Transition, and Chemotherapy Sensitivity of Pancreatic Cancer Cells

2020 ◽  
Author(s):  
Yan Xu ◽  
Yuhua Wei ◽  
Nanbin Liu ◽  
Deren Zhou ◽  
Rui Lin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Epithelial Mesenchymal Transition ◽  
Pancreatic Tumors ◽  
Luciferase Reporter ◽  
Protective Effects ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells

Abstract Objective: This study aims to explore the roles of miR-124 in pancreatic tumor and potential vehicles. Methods: The expression of miR-124 and EZH2 was determined in both pancreatic cancer tissues and cell lines. miR-124 or EZH2 was overexpressed in AsPC-1 and PANC1 cells. Then, the effects on cell viability. apoptosis, invasion, migration and epithelial mesenchymal transition were evaluated. Afterwards, the roles of miR-124 on the expression and function of EZH2 in pancreatic tumors were determined by dual luciferase reporter assay. Subsequently, miR-124 was transfected to bone marrow mesenchymal stromal cells (BM-MSCs), and the BM-MSCs derived exosomes were isolated and co-cultured with AsPC-1 and PANC1 cells, or injected into pancreatic cancer tumor-bearing mice. Results: The miR-124 expression levels decreased in pancreatic adenocarcinoma tissues and cancer cell lines AsPC-1, PANC1, BxPC-3 and SW1990. Furthermore, the elevated expression of miR-124 in AsPC-1 and PANC1 via miR-124 mimic transfection-induced apoptosis, metastasis and epithelial mesenchymal transition was suppressed, and the EZH2 overexpression partly reversed the protective effects of miR-124 against pancreatic tumors. In addition, the expression of miR-124 was detected in exosomes extracted from miR-124-transfected BM-MSCs, and these exosomes delivered miR-124 into pancreatic cancer cells, and presented the anti-tumor effects in vitro and in vivo. Conclusion: MiR-124-carried BM-MSC-derived exosomes have potential applications for the treatment of pancreatic tumors.

scholarly journals Differential mucin gene expression in human pancreatic and colon cancer cells

1991 ◽  
Vol 276 (3) ◽  
pp. 599-605 ◽  
Author(s):  
S Yonezawa ◽  
J C Byrd ◽  
R Dahiya ◽  
J J L Ho ◽  
J R Gum ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Northern Blots ◽  
Western Blots ◽  
Pancreatic Cancer Cells

The purpose of this study was to determine the quantity and nature of the mucins synthesized and secreted by four different pancreatic cancer cell lines. Well- to moderately-differentiated SW1990 and CAPAN-2 human pancreatic cancer cells were found to produce more high-Mr glycoprotein (HMG) than less-differentiated MIA PaCa-2 and PANC-1 cells. Most of the labelled HMG was secreted within 24 h. The results of chemical and enzymic degradation, ion-exchange chromatography and density-gradient centrifugation indicated that the HMG in SW1990 and CAPAN-2 cells has the properties expected for mucins, whereas much of the HMG in MIA PaCa-2 and PANC-1 cells may not be mucin, but proteoglycan. These results are consistent with immunoblots and Northern blots showing the presence of apomucin and apomucin mRNA in SW1990 and CAPAN-2 cells, but not in MIA PaCa-2 and PANC-1 cells. The Western blots and Northern blots also show that SW1990 and CAPAN-2 cells, like breast cancer cells, have the mammary-type apomucin and mRNA coded by the MUC1 gene, but lack the intestinal type apomucin and mRNA coded by the MUC2 gene. In contrast, the colon cancer cell lines tested in culture express apomucin and mRNA coded by MUC2 but not by MUC1.

scholarly journals Long Non-coding RNA DLEU2L Targets miR-210-3p to Suppress Gemcitabine Resistance in Pancreatic Cancer Cells via BRCA2 Regulation

2021 ◽  
Vol 8 ◽  
Author(s):  
Fei Xu ◽  
Heshui Wu ◽  
Jiongxin Xiong ◽  
Tao Peng
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Migration And Invasion ◽  
Pancreatic Cell ◽  
Clinical Issue ◽  
Pancreatic Cancer Cells

Gemcitabine (GEM) resistance remains a challenging clinical issue to overcome in chemotherapy against pancreatic cancer. We previously demonstrated that miR-210 derived from pancreatic cancer stem cells enhanced the GEM-resistant properties of pancreatic cancer cells, thus identifying miR-210 as an oncogenic miRNA. Herein, we report the existence of an upstream effector that acts as a competing endogenous RNA (ceRNA) to miR-210. Bioinformatic screening was performed to identify lncRNAs with a binding relationship to miR-210. Overexpression and interference vectors were constructed to demonstrate the effect of ceRNA activity in pancreatic cell behavior, both in vitro and in vivo. DLEU2L (deleted in lymphocytic leukemia 2-like), which is expressed at low levels in pancreatic cancer tissues, was shown to exhibit a binding relationship with miR-210-3p. Overexpression of DLEU2L and silencing of miR-210-3p suppressed the proliferation, migration, and invasion of pancreatic cancer cells while promoting apoptosis. These effects occurred via the inhibition of the Warburg effect (aerobic glycolysis) and AKT/mTOR signaling. In addition, we showed that BRCA2 is a target gene of miR-210-3p, and the downregulation of miR-210-3p by DLEU2L effectively induced an upregulation of BRCA2 via the ceRNA mechanism. In vivo, DLEU2L overexpression and miR-210-3p interference suppressed pancreatic tumor progression, consistent with the results of in vitro studies. The findings of our study establish DLEU2L as a ceRNA to miR-210-3p and reveal the critical role of the DLEU2L/miR-210-3p crosstalk in targeting GEM resistance.

Identification and characterization of CCK-B/gastrin receptors in human pancreatic cancer cell lines

1994 ◽  
Vol 266 (1) ◽  
pp. R277-R283 ◽  
Author(s):  
J. P. Smith ◽  
G. Liu ◽  
V. Soundararajan ◽  
P. J. McLaughlin ◽  
I. S. Zagon
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Human Pancreatic Cancer Cell ◽  
Pancreatic Cancer Cells

The gastrointestinal peptide cholecystokinin (CCK) is known to stimulate growth of human pancreatic cancer in a receptor-mediated fashion. The purpose of this study was to characterize the receptor responsible for the trophic effects of CCK in cancer cells. With the use of homogenates of PANC-1 human pancreatic cancer cells grown in vitro, the binding characteristics and optimal conditions of radiolabeled selective CCK-receptor antagonists ([3H]L-365,260 and [3H]L-364,718) were examined. Specific and saturable binding was detected with [3H]L-365,260, and Scatchard analysis revealed that the data were consistent for a single site of binding with a binding affinity of 4.3 +/- 0.6 nM and a binding capacity (Bmax) of 283 +/- 68 fmol/mg protein in log phase cells. Binding was dependent on protein concentration, time, temperature, and pH and was sensitive to Na+, K+, Mg2+, and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid. In contrast to log phase cells, Bmax decreased by 80 and 92% in confluent and postconfluent cultures, respectively. Subcellular fractionation studies revealed that binding was in the membrane fraction. Competition experiments indicated that L-365,260 and gastrin were more effective at displacing the radiolabeled L-365,260 than CCK. No binding was detected with the CCK-A antagonist [3H]L-364,718. Assays performed with [3H]L-365,260 on five additional human pancreatic cancer cell lines in vitro and tumor tissue from xenografts in nude mice also revealed specific and saturable binding. These results provide the first identification of a CCK-B/gastrin receptor in human pancreatic cancer cells and tumors and explain the effects of CCK on the growth of this malignancy.

Intra-Pancreatic Insulin Nourishes Cancer Cells: Do Insulin-Receptor Antagonists such as PGG and EGCG Play a Role?

2020 ◽  
Vol 48 (04) ◽  
pp. 1005-1019
Author(s):  
Lijuan Hu ◽  
Xijuan Chen ◽  
Shuai Qiu ◽  
Jing Yang ◽  
Hongyi Liu ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Insulin Receptor ◽  
Cancer Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Pancreatic Insulin ◽  
Igf1r Expression ◽  
Expression And Activity

Harboring insulin-producing cells, the pancreas has more interstitial insulin than any other organ. In vitro, insulin activates both insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) to stimulate pancreatic cancer cells. Whether intra-pancreatic insulin nourishes pancreatic cancer cells in vivo remains uncertain. In the present studies, we transplanted human pancreatic cancer cells orthotopically in euglycemic athymic mice whose intra-pancreatic insulin was intact or was decreased following pretreatment with streptozotocin (STZ). In the next eight weeks, the tumor carriers were treated with one of the IR/IGF1R antagonists penta-O-galloyl-[Formula: see text]-D-glucose (PGG) and epigallocatechin gallate (EGCG) or treated with vehicle. When pancreatic tumors were examined, their fraction occupied with living cells was decreased following STZ pretreatment and/or IR/IGF1R antagonism. Using Western blot, we examined tumor grafts for IR/IGF1R expression and activity. We also determined proteins that were downstream to IR/IGF1R and responsible for signal transduction, glycolysis, angiogenesis, and apoptosis. We demonstrated that STZ-induced decrease in intra-pancreatic insulin reduced IR/IGF1R expression and activity, decreased the proteins that promoted cell survival, and increased the proteins that promoted apoptosis. These suggest that intra-pancreatic insulin supported local cancer cells. When tumor carriers were treated with PGG or EGCG, the results were similar to those seen following STZ pretreatment. Thus, the biggest changes in examined proteins were usually seen when STZ pretreatment and PGG/EGCG treatment concurred. This suggests that intra-pancreatic insulin normally combated pharmacologic effects of PGG and EGCG. In conclusion, intra-pancreatic insulin nourishes pancreatic cancer cells and helps the cells resist IR/IGF1R antagonism.

scholarly journals Differential Gemcitabine Sensitivity in Primary Human Pancreatic Cancer Cells and Paired Stellate Cells Is Driven by Heterogenous Drug Uptake and Processing

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3628
Author(s):  
Manoj Amrutkar ◽  
Nils Tore Vethe ◽  
Caroline S. Verbeke ◽  
Monica Aasrum ◽  
Anette Vefferstad Finstadsveen ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Stellate Cells ◽  
Drug Uptake ◽  
Pancreatic Stellate Cells ◽  
Human Pancreatic Cancer ◽  
Pancreatic Cancer Cells ◽  
The Impact

Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed. Compared to PSCs, both the paired primary PCCs and cancer cell lines showed gemcitabine-induced dose-dependent cytotoxicity, high uptake, as well as high and variable intracellular levels of gemcitabine metabolites. PSCs were gemcitabine-resistant and demonstrated significantly lower drug uptake, which was not influenced by co-culturing with their paired PCCs. Expression of key gemcitabine regulators was variable, but overall strong in the cancer cells and significantly lower or undetectable in PSCs. In cancer cells, hENT1 inhibition significantly downregulated gemcitabine uptake and cytotoxicity, whereas DCK knockdown reduced cytotoxicity. In conclusion, heterogeneity in gemcitabine processing among different pancreatic cancer cells and stellate cells results from the differential expression of molecular regulators which determines the effect of gemcitabine.

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