Gemcitabine: Metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer

doi:10.1016/j.ejphar.2014.07.041

European Journal of Pharmacology

Volume 741, 15 October 2014, Pages 8-16

https://doi.org/10.1016/j.ejphar.2014.07.041 Get rights and content

Abstract

Gemcitabine is the first-line treatment for pancreatic adenocarcinoma, but is increasingly used to treat breast, bladder, and non-small cell lung cancers. Despite such broad use, intrinsic and acquired chemoresistance is common. In general, the underlying mechanisms of chemoresistance are poorly understood. Here, current knowledge of gemcitabine metabolism, mechanisms of action, sensitivity and chemoresistance reported over the past two decades are reviewed; and we also offer new perspectives to improve gemcitabine efficacy with particular reference to the treatment of pancreatic cancer.

Introduction

Gemcitabine is a nucleoside analog that has been used as a chemotherapeutic agent for more than 15 years. During this time gemcitabine has become the standard treatment choice for locally advanced and metastatic pancreatic cancer, for which there have been few treatment advances. Pancreatic cancer is one of the most devastating human cancers, with a median survival rate of less than 5 months after diagnosis and with under a 5% five-year survival rate even if brought under remission (Bilimoria et al., 2007). This poor prognosis is partly explained because of poor penetration of drugs into the dense and under vascularized tumour stroma (Neesse et al., 2011), a high degree of acquired chemoresistance by tumour cells and also because surgical intervention is not possible in almost 80% of patients (Vincent et al., 2011).

Gemcitabine is also used to treat a variety of solid tumors including breast, ovarian, and non-small cell lung cancer, especially when in combination with the platinum-based drugs cisplatin and carboplatin (Nagourney et al., 2008, Pfisterer et al., 2006, Reck et al., 2009). Despite its relatively broad and common use, mechanisms related to gemcitabine resistance are not well understood. A number of different cellular pathways, transcriptional factors and nucleotide metabolism enzymes have been linked to gemcitabine resistance and sensitivity.

Here the known molecular mechanisms commonly associated with gemcitabine pharmacokinetics and pharmacodynamics are reviewed with a special focus on pancreatic cancer. A better understanding of gemcitabine pharmacology is essential for developing improved treatments and ultimately for increasing patient survival in pancreatic cancer.

Section snippets

Uptake and metabolism

Gemcitabine (2′,2′-difluoro-2′-deoxycytidine; dFdC) is a deoxycytidine analog with multiple modes of action inside the cell. The basics of gemcitabine metabolism are illustrated in Fig. 1. As a prodrug, dFdC must be metabolized to the active triphosphate form of gemcitabine (2′,2′-difluoro-2′-deoxycytidine triphosphate; dFdCTP). Cellular uptake of gemcitabine is mediated by a family of integral membrane proteins termed human nucleoside transporters (hNTs), which overcome the inherent barrier to

Mechanisms of action

The most important mechanism of action of gemcitabine is inhibition of DNA synthesis (Huang et al., 1991). When dFdCTP is incorporated into DNA, a single deoxynucleotide is incorporated afterwards, preventing chain elongation (Gandhi et al., 1996). This non-terminal position of gemcitabine makes DNA polymerases unable to proceed, in a process known as ‘masked chain-termination′, which also inhibits removal of gemcitabine by DNA repair enzymes (Huang et al., 1991). This process is shown in Fig. 2

Gemcitabine chemoresistance and sensitivity

Like many other drugs used in cancer chemotherapy, resistance to gemcitabine may be intrinsic, or acquired by individual patient during treatment cycles. Several mechanisms have been reported in the literature and some of these seem well established (Table 1). However, as many of these processes are complex, it can be difficult to understand precise roles and, indeed, consequences in chemoresistance. This is particularly relevant for signalling pathways involved in apoptosis, growth,

Perspectives

Gemcitabine is still the standard chemotherapeutic agent of choice to treat pancreatic cancer; with the best patient clinical outcome, and this is unlikely to change in the coming years. However, few improvements have been made in gemcitabine-based chemotherapies for pancreatic and other cancers (e.g. breast, ovarian and non-small cell lung cancer), although combination therapies are likely to emerge as realistic treatment choices, especially for pancreatic cancer. A recent phase III study of

Conclusion

Many important molecular targets and pathways related to gemcitabine chemoresistance and sensitivity are now established; however, their precise mechanisms of action are not completely understood in most cases. Different pathways and molecular interactions have been described in recent years and new roles for some relatively well-known chemoresistance markers (e.g. NF-κB) have been discovered. Gemcitabine still has clinical potential to treat a broad spectrum of human cancers, but the

Acknowledgments

Financial support was provided by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP – Grants 2009/01303-1 and 2011/04938-8) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). We thank Dr PF Long from King׳s College London and Faculdade de Ciências Farmacêuticas, Universidade de São Paulo for his critical comments.

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ReviewGemcitabine: Metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer

Abstract

Introduction

Section snippets

Uptake and metabolism

Mechanisms of action

Gemcitabine chemoresistance and sensitivity

Perspectives

Conclusion

Acknowledgments

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Cytosolic 5’-nucleotidase III (NT5C3): gene sequence variation and functional genomics

Pharmacogenet. Genomics

Role of NF-kappaB and Akt/PI3K in the resistance of pancreatic carcinoma cell lines against gemcitabine-induced cell death

Oncogene

Combination of hedgehog signaling blockage and chemotherapy leads to tumor reduction in pancreatic adenocarcinomas

Pancreas

Sonic hedgehog promotes desmoplasia in pancreatic cancer

Clin. Cancer Res.

Successful treatment with nab-paclitaxel and gemcitabine after FOLFIRINOX failure in a patient with metastasized pancreatic adenocarcinoma

Onkologie

In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant

Cancer Res.

Validation of the 6th edition AJCC pancreatic cancer staging system: report from the national cancer database

Cancer

The role of HuR in gemcitabine efficacy in pancreatic cancer: HuR Up-regulates the expression of the gemcitabine metabolizing enzyme deoxycytidine kinase

Cancer Res.

FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer

N. Engl. J. Med.

Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy

Oncogene

An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines

Cancer Res.

RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine

Oncogene

The antiproliferative activity of DMDC is modulated by inhibition of cytidine deaminase

Cancer Res.

HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

J. Exp. Med.

Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer

Cancer Chemother. Pharmacol.

Chemotherapy triggers apoptosis in a caspase-8-dependent and mitochondria-controlled manner in the non-small cell lung cancer cell line NCI-H460

Cancer Res.

Is the resistance of gemcitabine for pancreatic cancer settled only by overexpression of deoxycytidine kinase?

Oncol. Rep.

Roles of HMGA proteins in cancer

Nat. Rev. Cancer

Excision of 2′,2′-difluorodeoxycytidine (gemcitabine) monophosphate residues from DNA

Cancer Res.

Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine

Cancer Res.

Impact of FOLFIRINOX compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/ACCORD 11 randomized trial

J. Clin. Oncol.

Comparison of the cellular pharmacokinetics and toxicity of 2′,2′-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine

Cancer

Cellular elimination of 2′,2′-difluorodeoxycytidine 5′-triphosphate: a mechanism of self-potentiation

Cancer Res.

Review
Gemcitabine: Metabolism and molecular mechanisms of action, sensitivity and chemoresistance in pancreatic cancer