Prognostic Implications of Expression Profiling for Gemcitabine-Related Genes (hENT1, dCK, RRM1, RRM2) in Patients With Resectable Pancreatic Adenocarcinoma Receiving Adjuvant Chemotherapy

Sierżęga, Marek; Pach, Radosław; Kulig, Piotr; Legutko, J; Kulig, Jan

doi:10.1097/mpa.0000000000000807

Cited by 34 publications

(32 citation statements)

References 21 publications

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“…Currently the functional significance of PKMYT1 in prostate cancer remains unclear, and it makes sense to determine whether PKYMT1 is indispensable in prostate cancer, which requires further investigation. The ribonucleotide reductase M2 subunit (RRM2) plays important role in several human cancers, including colorectal cancer, hepatocellular carcinoma, pancreatic adenocarcinoma, and breast cancer (Lee et al, 2014;Sierzega et al, 2017;Nana et al, 2018;Chen et al, 2019). Increased expression of RRM2 has been demonstrated to be a mechanism driving poor patient outcomes in prostate cancer, in accordance with our findings (Mazzu et al, 2019).…”

Section: Discussionsupporting

confidence: 88%

Integrative Analysis of MicroRNA and Gene Interactions for Revealing Candidate Signatures in Prostate Cancer

et al. 2020

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MicroRNA (miRNA)-gene interactions are well-recognized as involved in the progression of almost all cancer types including prostate cancer, which is one of the most common cancers in men. This study explored the significantly dysregulated genes and miRNAs and elucidated the potential miRNA-gene regulatory network in prostate cancer. Integrative analysis of prostate cancer and normal prostate transcriptomic data in The Cancer Genome Atlas dataset was conducted using both differential expression analysis and weighted correlation network analysis (WGCNA). Thirteen genes (RRM2,

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Section: Discussionsupporting

confidence: 88%

Integrative Analysis of MicroRNA and Gene Interactions for Revealing Candidate Signatures in Prostate Cancer

et al. 2020

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“…Some reports have indicated that when GEM was administered iv, the hENT1 expression level correlated with the anticancer effects of GEM, such as overall survival and disease‐free survival (Maréchal et al, , ; Nakagawa et al, ; Sierzega et al, ), whereas our results indicated that hENT2 would have a more important role in GEM uptake by metastatic tumor in GEM‐HAI therapy. This discrepancy is probably due to the difference in the administration route of GEM, because the topical concentration of GEM in metastatic tumor is much higher in GEM‐HAI therapy than in iv administration.…”

Section: Discussioncontrasting

confidence: 44%

“…The precise reasons for these differences are unclear, though it is known that the expression and activity of metabolic enzymes and transporters are different among different cell types, such as normal and cancer cells or cells from different tissues. Clinical studies have also found individual differences in the expression levels of transporters, such as hENT1, hENT2, and hCNT3, and metabolic enzymes, such as ribonucleotide reductase M1 and deoxycytidine kinase (Sierzega, Pach, Kulig, Legutko, & Kulig, ). Since the origin of the pancreatic cancer cells used in this study was different (MIA‐PaCa2 cells were primary tumor cells and As‐PC1 cells were metastatic tumor cells of pancreatic adenocarcinoma), the disparity probably resulted from the different cell types (Pennycooke et al, ).…”

Section: Discussionmentioning

confidence: 99%

Contribution of equilibrative nucleoside transporters 1 and 2 to gemcitabine uptake in pancreatic cancer cells

Hioki

Shimada

Tian

et al. 2018

Biopharm & Drug Disp

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Hepatic arterial infusion (HAI) chemotherapy is expected to be a more effective and safer method to treat the hepatic metastasis of pancreatic cancer than intravenous (iv) administration because of higher tumor exposure and lower systemic exposure. To clarify the uptake mechanism of nucleoside anticancer drugs, including gemcitabine (GEM), in pancreatic cancer, we investigated the uptakes of radiolabeled uridine (a general substrate of nucleoside transporters) and GEM in pancreatic cancer cell lines MIA-PaCa2 and As-PC1. Uridine uptake was inhibited by non-labeled GEM and also by S-(4-nitrobenzyl)-6-thioinosine (NBMPR; an inhibitor of equilibrative nucleoside transporters, ENTs) in a concentration-dependent manner, suggesting that ENTs contribute to uridine uptake in pancreatic cancer cells. As for GEM, saturable uptake was mediated by high- and low-affinity components with K values of micromolar and millimolar orders, respectively. Uptake was inhibited in a concentration-dependent manner by NBMPR and was sodium ion-independent. Moreover, the concentration dependence of uptake in the presence of 0.1 μM NBMPR showed a single low-affinity site. These results indicated that the high- and low-affinity sites correspond to hENT1 and hENT2, respectively. The results indicated that at clinically relevant hepatic concentrations of GEM in GEM-HAI therapy, the metastatic tumor exposure of GEM is predominantly determined by hENT2 under unsaturated conditions, suggesting that hENT2 expression in metastatic tumor would be a candidate biomarker for indicating anticancer therapy with GEM-HAI.

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“…8,9) The lack of equilibrative nucleoside transporter 1 (ENT1) and deoxycytidine kinase (dCK) and increase in the levels of ribonucleotide reductase subunits M1 (RRM1) and M2 (RRM2) are involved in the development of gemcitabine resistance. [10][11][12][13] Furthermore, a clinical study reported that the expression of these four key genes influences the prognosis of patients with pancreatic cancer undergoing adjuvant chemotherapies. 14) ENT1 is a cellular transporter involved in the intracellular incorporation of gemcitabine.…”

Section: Discussionmentioning

confidence: 99%

Anti-tumor Activities of 3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors and Bisphosphonates in Pancreatic Cell Lines Which Show Poor Responses to Gemcitabine

Kawashiri

Tokunaga

Kobayashi

et al. 2020

Biological & Pharmaceutical Bulletin

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Few therapeutic options exist for gemcitabine-resistant pancreatic cancer. In this study, we investigated the anti-cancer effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors and bisphosphonates in pancreatic cancer cell lines (SUIT-2 and MIA PaCa-2) which show poor responses to gemcitabine, established through long-term culture in nutrient-deprived or gemcitabine-containing media. Under the nutrientdeprived condition, IC 50 s for statins and bisphosphonates decreased and those for gemcitabine increased compared with those under normal conditions. In cells cultured long-term with gemcitabine, although IC 50 s for gemcitabine increased, those for statins and bisphosphonates either slightly increased or remained unchanged. Thus, these drugs may be effective against pancreatic cancer cells which show poor responses to gemcitabine.

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Prognostic Implications of Expression Profiling for Gemcitabine-Related Genes (hENT1, dCK, RRM1, RRM2) in Patients With Resectable Pancreatic Adenocarcinoma Receiving Adjuvant Chemotherapy

Abstract: Expression of hENT, RRM1, and dCK genes provides important prognostic information for PDAC patients treated with adjuvant gemcitabine.

Cited by 34 publications

References 21 publications

Integrative Analysis of MicroRNA and Gene Interactions for Revealing Candidate Signatures in Prostate Cancer

Integrative Analysis of MicroRNA and Gene Interactions for Revealing Candidate Signatures in Prostate Cancer

Contribution of equilibrative nucleoside transporters 1 and 2 to gemcitabine uptake in pancreatic cancer cells

Anti-tumor Activities of 3-Hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) Reductase Inhibitors and Bisphosphonates in Pancreatic Cell Lines Which Show Poor Responses to Gemcitabine

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