Pharmacogenetics and pharmacoepigenetics of gemcitabine

Candelaria, Myrna; Cruz-Hernandez, Erik de la; Pérez-Cárdenas, Enrique; Trejo-Becerril, Catalina; Gutiérrez-Hernández, Olga; Dueñas‐González, Alfonso

doi:10.1007/s12032-009-9349-y

Cited by 24 publications

(19 citation statements)

References 86 publications

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“…Gemcitabine (2′,2′-difluorodeoxycytidine, dFdC) HCl is approved for the treatment of a wide spectrum of solid tumors including pancreatic, non-small-cell lung cancer, breast, and bladder cancers (Candelaria, M. et al, 2010; Barton-Burke 1999; Kalykaki et al, 2008; Sandler et al, 2000; Zucali et al, 2008; Cetina et al, 2004; Candelaria, Myrna et al, 2007). However, tumor cells often acquire resistance during or after gemcitabine treatment (Bergman, Andries M. et al, 2002; Andersson et al, 2009; Sezgin et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro evaluation of novel lipophilic monophosphorylated gemcitabine derivatives and their nanoparticles

Lansakara-P

Rodriguez

Cui

2012

International Journal of Pharmaceutics

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Gemcitabine hydrochloride (HCl) is approved for the treatment of a wide spectrum of solid tumors. However, the rapid development of resistance often makes gemcitabine less efficacious. In the present study, we synthesized several novel lipophilic monophosphorylated gemcitabine derivatives, incorporated them into solid lipid nanoparticles, and then evaluated their ability to overcome major known gemcitabine resistance mechanisms by evaluating their in vitro cytotoxicities in cancer cells that are deficient in deoxycytidine kinase (dCK), deficient in human equilibrative nucleoside transporter (hENT1), over-expressing ribonucleotide reductase M1 subunit (RRM1), or over-expressing RRM2. In dCK deficient cells, the monophosphorylated gemcitabine derivatives and their nanoparticles were up to 86-fold more cytotoxic than gemcitabine HCl. The majority of the gemcitabine derivatives and their nanoparticles were more cytotoxic than gemcitabine HCl in cells that over-expressing RRM1 or RRM2, and the gemcitabine derivatives in nanoparticles were also resistant to deamination by deoxycytidine deaminase. The gemcitabine derivatives (in nanoparticles) hold a great potential in overcoming gemcitabine resistance.

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Section: Introductionmentioning

confidence: 99%

Synthesis and in vitro evaluation of novel lipophilic monophosphorylated gemcitabine derivatives and their nanoparticles

Lansakara-P

Rodriguez

Cui

2012

International Journal of Pharmaceutics

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“…Gemcitabine's pharmacological characteristics are unique in that two main classes of genes are essential for its antitumor effects and resistance: membrane transporter protein-coding genes, whose products are responsible for drug intracellular uptake, and drug metabolism-coding genes, which catalyze its activation and inactivation [4]. Thus, the expression of these genes is key for tumor response and resistance to gemcitabine.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation-Independent Reversion of Gemcitabine Resistance by Hydralazine in Cervical Cancer Cells

et al. 2012

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Background Down regulation of genes coding for nucleoside transporters and drug metabolism responsible for uptake and metabolic activation of the nucleoside gemcitabine is related with acquired tumor resistance against this agent. Hydralazine has been shown to reverse doxorubicin resistance in a model of breast cancer. Here we wanted to investigate whether epigenetic mechanisms are responsible for acquiring resistance to gemcitabine and if hydralazine could restore gemcitabine sensitivity in cervical cancer cells. Methodology/Principal Findings The cervical cancer cell line CaLo cell line was cultured in the presence of increasing concentrations of gemcitabine. Down-regulation of hENT1 & dCK genes was observed in the resistant cells (CaLoGR) which was not associated with promoter methylation. Treatment with hydralazine reversed gemcitabine resistance and led to hENT1 and dCK gene reactivation in a DNA promoter methylation-independent manner. No changes in HDAC total activity nor in H3 and H4 acetylation at these promoters were observed. ChIP analysis showed H3K9m2 at hENT1 and dCK gene promoters which correlated with hyper-expression of G9A histone methyltransferase at RNA and protein level in the resistant cells. Hydralazine inhibited G9A methyltransferase activity in vitro and depletion of the G9A gene by iRNA restored gemcitabine sensitivity. Conclusions/Significance Our results demonstrate that acquired gemcitabine resistance is associated with DNA promoter methylation-independent hENT1 and dCK gene down-regulation and hyper-expression of G9A methyltransferase. Hydralazine reverts gemcitabine resistance in cervical cancer cells via inhibition of G9A histone methyltransferase.

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“…miRNAs have also been found to affect the absorption and excretion of small molecules through SLC proteins. Folate, nucleoside and amino acid transporters all belong to the SLC transporter family and mediate the uptake of hydrophilic drugs such as gemcitabine and other nucleoside analogues (Candelaria et al, 2010). These levels of membrane transporters are also regulated by miRNA.…”

Section: Micrornas Regulate the Expression Of Transporter Proteinsmentioning

confidence: 99%

The effects of microRNA on the absorption, distribution, metabolism and excretion of drugs

Chevillet

Liu

et al. 2014

British J Pharmacology

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The importance of genetic factors (e.g. sequence variation) in the absorption, distribution, metabolism, excretion (ADME) and overall efficacy of therapeutic agents is well established. Our ability to identify, interpret and utilize these factors is the subject of much clinical investigation and therapeutic development. However, drug ADME and efficacy are also heavily influenced by epigenetic factors such as DNA/histone methylation and non-coding RNAs [especially microRNAs (miRNAs)]. Results from studies using tools, such as in silico miRNA target prediction, in vitro functional assays, nucleic acid profiling/sequencing and high-throughput proteomics, are rapidly expanding our knowledge of these factors and their effects on drug metabolism. Although these studies reveal a complex regulation of drug ADME, an increased understanding of the molecular interplay between the genome, epigenome and transcriptome has the potential to provide practically useful strategies to facilitate drug development, optimize therapeutic efficacy, circumvent adverse effects, yield novel diagnostics and ultimately become an integral component of personalized medicine. LINKED ARTICLESThis article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2015.172.issue-11 Abbreviations ABC, ATP-binding cassette; ABCB1/MDR1/P-gp, multidrug resistance protein 1/P-glycoprotein; ADME, absorption, distribution, metabolism, excretion; antimiR, miRNA antagonist; CYP450, cytochrome P450; DOX, doxorubicin; ESR1, oestrogen receptor alpha; ETS1, V-Ets avian erythroblastosis virus E26 oncogene homologue 1; GPX7, glutathione peroxidase 7; GSS, glutathione synthetase; HDAC, histone deacetylase; LXRA, liver X receptor α; miRNA, microRNA; mRNA, messenger RNA; ncRNA, non-coding RNA; NR1C1, PPARα; PK, pharmacokinetic; PXR, pregnane X receptor; RISC, RNA-induced silencing complex; RXR, retinoid X receptor; SLC, solute carrier; UGT, UDP-glucuronosyltransferase; UTR, untranslated region; VD receptor, vitamin D receptor The proper control of absorption, distribution, metabolism and excretion (ADME) of xenobiotics is essential for living organisms to obtain energy, acquire necessary building blocks (e.g. essential amino acids) and maintain homeostasis in a complex chemical environment. Genes involved in ADME activities encode various receptor/transporters, biotransformation enzymes and accessory proteins (PharmaADME, http://pharmaadme.org/joomla/). These proteins include membrane transporters responsible for the absorption and excretion of specific molecules and enzymes to convert xenobiotics for excretion. To date, over 300 transporters and enzymes directly involved in ADME process have been described. This long list of components makes the study of ADME inherently complex, as transporters and enzymes work in concert to respond dynamically to diverse external factors. Despite the formidable complexity of the field, an understanding of ADME is critical for drug development in order...

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Pharmacogenetics and pharmacoepigenetics of gemcitabine

Cited by 24 publications

References 86 publications

Synthesis and in vitro evaluation of novel lipophilic monophosphorylated gemcitabine derivatives and their nanoparticles

Synthesis and in vitro evaluation of novel lipophilic monophosphorylated gemcitabine derivatives and their nanoparticles

DNA Methylation-Independent Reversion of Gemcitabine Resistance by Hydralazine in Cervical Cancer Cells

The effects of microRNA on the absorption, distribution, metabolism and excretion of drugs

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