Promising molecular mechanisms responsible for gemcitabine resistance in cancer

Jia, Yanfei; Xie, Jingwu

doi:10.1016/j.gendis.2015.07.003

Cited by 128 publications

(118 citation statements)

References 72 publications

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“…Gemcitabine is the standard-of-care chemotherapeutics for treating pancreatic cancer (PaCA), however is subjected to high occurrences of drug resistance largely because of induced epithelial-mesenchymal transition and eventually tumor metastasis. 39,40 Therefore, combining drugs capable of inhibiting epithelial-mesenchymal transition appears to be a viable solution to Gem resistance, 41 and one potential candidate is fibroblast growth factor receptor (FGFR) inhibitors. 42,43 We have discovered that Gemcitabine combining BGJ398, an FGFR inhibitor, 44 significantly suppressed cell growth/mobility and triggered sustained cell cycle arrest in Gem-resistant human PaCA cell lines (i.e., MIA-RG8).…”

Section: Resultsmentioning

confidence: 99%

An IonStar Experimental Strategy for MS1 Ion Current-Based Quantification Using Ultrahigh-Field Orbitrap: Reproducible, In-Depth, and Accurate Protein Measurement in Large Cohorts

Shen

et al. 2017

J. Proteome Res.

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In-depth and reproducible protein measurement in many biological samples is often critical for pharmaceutical/biomedical proteomics but remains challenging. MS1-based quantification using quadrupole/ultrahigh-field Orbitrap (Q/UHF-Orbitrap) holds great promise, but the critically important experimental approaches enabling reliable large-cohort analysis have long been overlooked. Here we described an IonStar experimental strategy achieving excellent quantitative quality of MS1 quantification. Key features include: (i) an optimized, surfactant-aided sample preparation approach provides highly efficient (>75% recovery) and reproducible (<15% CV) peptide recovery across large cell/tissue cohorts; (ii) a long column with modest gradient length (2.5 h) yields the optimal balance of depth/throughput on a Q/UHF-Orbitrap; (iii) a large-ID trap not only enables highly reproducible gradient delivery as for the first time observed via real-time conductivity monitoring, but also increases quantitative loading capacity by >8-fold and quantified >25% more proteins; (iv) an optimized HCD-OT markedly outperforms HCD-IT when analyzing large cohorts with high loading amounts; (v) selective removal of hydrophobic/hydrophilic matrix components using a novel selective trapping/delivery approach enables reproducible, robust LC–MS analysis of >100 biological samples in a single set, eliminating batch effect; (vi) MS1 acquired at higher resolution (fwhm = 120 k) provides enhanced S/N and quantitative accuracy/precision for low-abundance species. We examined this pipeline by analyzing a 5 group, 20 samples biological benchmark sample set, and quantified 6273 unique proteins (≥2 peptides/protein) under stringent cutoffs without fractionation, 6234 (>99.4%) without missing data in any of the 20 samples. The strategy achieved high quantitative accuracy (3–6% media error), low intragroup variation (6–9% media intragroup CV) and low false-positive biomarker discovery rates (3–8%) across the five groups, with quantified protein abundances spanning >6.5 orders of magnitude. Finally, this strategy is straightforward, robust, and broadly applicable in pharmaceutical/biomedical investigations.

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Section: Resultsmentioning

confidence: 99%

An IonStar Experimental Strategy for MS1 Ion Current-Based Quantification Using Ultrahigh-Field Orbitrap: Reproducible, In-Depth, and Accurate Protein Measurement in Large Cohorts

Shen

et al. 2017

J. Proteome Res.

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“…CM03 also down-regulates the oncogenic Gli transcription factors Gli2/4, downstream of TEAD and highly up regulated in PDAC. 6 As Gli2 is essential for KRAS-driven oncogenesis in vivo 53 and plays a role in PDAC resistance to both gemcitabine 54 and BET inhibitors, 55 this suggests CM03 may have a novel therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

“…In the noncanonical Hh-mediated gemcitabine resistance pathway the transcript levels of SMO and GLI1 are also down-regulated by CM03. 54 Tumor associated macrophages and cancer-associated myofibroblasts in tissue stroma are also key drivers for chemoresistance in PDAC, and it is notable that IGF2 and SHC2 are down-regulated by CM03 as these proteins have been implicated in insulin receptor-mediated chemoresistance. 71 Collectively, these findings clearly demonstrate the ability of CM03 to simultaneously target several fundamental PDAC tumorigenesis mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule

et al. 2018

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Human pancreatic ductal adenocarcinoma (PDAC) involves the dysregulation of multiple signaling pathways. A novel approach to the treatment of PDAC is described, involving the targeting of cancer genes in PDAC pathways having over-representation of G-quadruplexes, using the trisubstituted naphthalene diimide quadruplex-binding compound 2,7-bis(3-morpholinopropyl)-4-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (CM03). This compound has been designed by computer modeling, is a potent inhibitor of cell growth in PDAC cell lines, and has anticancer activity in PDAC models, with a superior profile compared to gemcitabine, a commonly used therapy. Whole-transcriptome RNA-seq methodology has been used to analyze the effects of this quadruplex-binding small molecule on global gene expression. This has revealed the down-regulation of a large number of genes, rich in putative quadruplex elements and involved in essential pathways of PDAC survival, metastasis, and drug resistance. The changes produced by CM03 represent a global response to the complexity of human PDAC and may be applicable to other currently hard-to-treat cancers.

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“…Regarding antimetabolites 5-FU, gemcitabine, and methotrexate used in the present study, increased expression of thymidylate synthase, which is the target of 5-FU, was shown to be a resistance mechanism to 5-FU [ 41 ]. Dysregulation of the enzymes participating in the gemcitabine metabolic pathway is one of the mechanisms responsible for gemcitabine resistance [ 42 ]. Amplification of the dihydrofolate reductase (DHFR) gene resulting in increased levels of the enzyme was identified as one mechanism of acquired methotrexate resistance [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Chemotherapeutics-induced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer

Shieh

Wang

et al. 2016

Oncotarget

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Cancer cells initially characterized as sensitive to chemotherapy may acquire resistance to chemotherapy and lead to tumor recurrence through the expansion of drug-resistant population. Acquisition of drug resistance to conventional chemotherapy is a major obstacle in the treatment of recurrent cancer. Here we investigated whether anticancer drugs induced Oct4 expression, thereby contributing to acquired drug resistance and tumor recurrence in bladder cancer. We identified a positive correlation of Oct4 expression with tumor recurrence in 122 clinical specimens of superficial high-grade (stages T1-2) bladder transitional cell carcinoma (TCC). Increased Oct4 levels in bladder tumors were associated with short recurrence-free intervals in the patients. Chemotherapy induced Oct4 expression in bladder cancer cells. Notably, treatment with cisplatin increased CD44-positive bladder cancer cells expressing Oct4, representing cancer stem-like cell subpopulation. Forced expression of Oct4 reduced, whereas knockdown of Oct4 enhanced, drug sensitivity in bladder cancer cells. Furthermore, tumor cells overexpressing Oct4 responded poorly to cisplatin in vivo. In regard to clinical relevance, inhibition of Oct4 by all-trans retinoic acid (ATRA) synergistically increased sensitivity to cisplatin in bladder cancer cells. Furthermore, the combination of cisplatin and ATRA was superior to cisplatin alone in suppressing tumor growth. Therefore, our results provide evidence that Oct4 increases drug resistance and implicate that inhibition of Oct4 may be a therapeutic strategy to circumvent drug resistance.

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Promising molecular mechanisms responsible for gemcitabine resistance in cancer

Cited by 128 publications

References 72 publications

An IonStar Experimental Strategy for MS1 Ion Current-Based Quantification Using Ultrahigh-Field Orbitrap: Reproducible, In-Depth, and Accurate Protein Measurement in Large Cohorts

An IonStar Experimental Strategy for MS1 Ion Current-Based Quantification Using Ultrahigh-Field Orbitrap: Reproducible, In-Depth, and Accurate Protein Measurement in Large Cohorts

Targeting Multiple Effector Pathways in Pancreatic Ductal Adenocarcinoma with a G-Quadruplex-Binding Small Molecule

Chemotherapeutics-induced Oct4 expression contributes to drug resistance and tumor recurrence in bladder cancer

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