Promising molecular mechanisms responsible for gemcitabine resistance in cancer

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Abstract

Gemcitabine is the first-line treatment for pancreatic ductual adenocarcinoma (PDAC) as well as acts against a wide range of other solid tumors. Patients usually have a good initial response to gemcitabine-based chemotherapy but would eventually develop resistance. To improve survival and prognosis of cancer patients, better understanding of the mechanisms responsible for gemcitabine resistance and discovery of new therapeutic strategies are in great need. Amounting evidence indicate that the developmental pathways, such as Hedgehog (Hh), Wnt and Notch, become reactivated in gemcitabine-resistant cancer cells. Thus, the strategies for targeting these pathways may sensitize cancer cells to gemcitabine treatment. In this review, we will summarize recent development in this area of research and discuss strategies to overcome gemcitabine resistance. Given the cross-talk between these three developmental signaling pathways, designing clinical trials using a cocktail of inhibitory agents targeting all these pathways may be more effective. Ultimately, our hope is that targeting these developmental pathways may be an effective way to improve the gemcitabine treatment outcome in cancer patients.

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Identification of pancreatic cancer stem cells.

Chenwei Li, David G Heidt, Piero Dalerba … (2007)

Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44(+)CD24(+)ESA(+) phenotype (0.2-0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44(+)CD24(+)ESA(+) cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44(+)CD24(+)ESA(+) pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44(+)CD24(+)ESA(+) pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.

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Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.

H von der Maase, S W Hansen, J Roberts … (2000)

Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) were compared in patients with locally advanced or metastatic transitional-cell carcinoma (TCC) of the urothelium. Patients with stage IV TCC and no prior systemic chemotherapy were randomized to GC (gemcitabine 1,000 mg/m2 days 1, 8 and 15; cisplatin 70 mg/m2 day 2) or standard MVAC every 28 days for a maximum of six cycles. Four hundred five patients were randomized (GC, n = 203; MVAC, n = 202). The groups were well-balanced with respect to prognostic factors. Overall survival was similar on both arms (hazards ratio [HR], 1.04; 95% confidence interval [CI], 0.82 to 1.32; P = .75), as were time to progressive disease (HR, 1.05; 95% CI, 0.85 to 1.30), time to treatment failure (HR, 0.89; 95% CI 0.72 to 1.10), and response rate (GC, 49%; MVAC, 46%). More GC patients completed six cycles of therapy, with fewer dose adjustments. The toxic death rate was 1% on the GC arm and 3% on the MVAC arm. More GC than MVAC patients had grade 3/4 anemia (27% v 18%, respectively), and thrombocytopenia (57% v 21%, respectively). On both arms, the RBC transfusion rate was 13 of 100 cycles and grade 3/4 hemorrhage or hematuria was 2%; the platelet transfusion rate was four patients per 100 cycles and two patients per 100 cycles on GC and MVAC, respectively. More MVAC patients, compared with GC patients, had grade 3/4 neutropenia (82% v 71%, respectively), neutropenic fever (14% v 2%, respectively), neutropenic sepsis (12% v 1%, respectively), and grade 3/4 mucositis (22% v 1%, respectively) and alopecia (55% v 11%, respectively). Quality of life was maintained during treatment on both arms; however, more patients on GC fared better regarding weight, performance status, and fatigue. GC provides a similar survival advantage to MVAC with a better safety profile and tolerability. This better-risk benefit ratio should change the standard of care for patients with locally advanced and metastatic TCC from MVAC to GC.

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Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.

Zhiwei Wang, Yiwei Li, Dejuan Kong … (2009)

Despite rapid advances in many fronts, pancreatic cancer (PC) remains one of the most difficult human malignancies to treat due, in part, to de novo and acquired chemoresistance and radioresistance. Gemcitabine alone or in combination with other conventional therapeutics is the standard of care for the treatment of advanced PC without any significant improvement in the overall survival of patients diagnosed with this deadly disease. Previous studies have shown that PC cells that are gemcitabine-resistant (GR) acquired epithelial-mesenchymal transition (EMT) phenotype, which is reminiscent of "cancer stem-like cells"; however, the molecular mechanism that led to EMT phenotype has not been fully investigated. The present study shows that Notch-2 and its ligand, Jagged-1, are highly up-regulated in GR cells, which is consistent with the role of the Notch signaling pathway in the acquisition of EMT and cancer stem-like cell phenotype. We also found that the down-regulation of Notch signaling was associated with decreased invasive behavior of GR cells. Moreover, down-regulation of Notch signaling by siRNA approach led to partial reversal of the EMT phenotype, resulting in the mesenchymal-epithelial transition, which was associated with decreased expression of vimentin, ZEB1, Slug, Snail, and nuclear factor-kappaB. These results provide molecular evidence showing that the activation of Notch signaling is mechanistically linked with chemoresistance phenotype (EMT phenotype) of PC cells, suggesting that the inactivation of Notch signaling by novel strategies could be a potential targeted therapeutic approach for overcoming chemoresistance toward the prevention of tumor progression and/or treatment of metastatic PC.

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Author and article information

Contributors

Yanfei Jia

Jingwu Xie

Journal

Journal ID (nlm-ta): Genes Dis

Journal ID (iso-abbrev): Genes Dis

Title: Genes & Diseases

Publisher: Chongqing Medical University

ISSN (Print): 2352-4820

ISSN (Electronic): 2352-3042

Publication date PMC-release: 30 July 2015

Publication date Collection: December 2015

Publication date (Electronic): 30 July 2015

Volume: 2

Issue: 4

Pages: 299-306

Affiliations

[a ]Central Laboratory, Jinan Central Hospital Affiliated to Shandong University, Jinan 250013, China

[b ]Division of Hematology and Oncology, Department of Pediatrics, Wells Center for Pediatric Research, Indiana University Simon Cancer Center, Indiana University, Indianapolis, IN 46202, USA

Author notes

[∗ ]Corresponding authors. jiayanfei_@ 123456126.com jinxie@ 123456iupui.edu

Article

Publisher ID: S2352-3042(15)00045-8

DOI: 10.1016/j.gendis.2015.07.003

PMC ID: 6150077

PubMed ID: 30258872

SO-VID: 89103a9b-e651-46b3-b8c7-4aa5e1c5d1c8

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 14 June 2015

Date accepted : 20 July 2015

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Promising molecular mechanisms responsible for gemcitabine resistance in cancer

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Genes & Diseases

Most cited references 63

Identification of pancreatic cancer stem cells.

Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study.

Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway.

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Cited by 66

Most referenced authors 1,116