ArticlePloS one2012
DNA methylation-independent reversion of gemcitabine resistance by hydralazine in cervical cancer cells.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 51 citations in OpenAlex.
- Extracellular Vesicle-Mediated Regulation of H3C14 Contributes to Gemcitabine Resistance in Bladder Cancer.Journal of extracellular vesicles · 2025Article
- DNMT Enzymes and Their Impact on Cervical Cancer: A State-of-the-Art Review.International journal of molecular sciences · 2025Review
- Review
- Review
- Cell-type dependent regulation of pluripotency and chromatin remodeling genes by hydralazine.Stem cell research & therapy · 2023Article
- Combination treatment with hENT1 and miR-143 reverses gemcitabine resistance in triple-negative breast cancer.Cancer cell international · 2022Article
- DNA Methylation Malleability and Dysregulation in Cancer Progression: Understanding the Role of PARP1.Biomolecules · 2022Review
- The Class I HDAC Inhibitor Valproic Acid Strongly Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Immune System Activation.Biomedicines · 2022Article
- Drug resistance to nelarabine in leukemia cell lines might be caused by reduced expression of deoxycytidine kinase through epigenetic mechanisms.Cancer chemotherapy and pharmacology · 2022Article
- Recent progress in DNA methyltransferase inhibitors as anticancer agents.Frontiers in pharmacology · 2022Review
- Inhibitors of DNA Methylation.Advances in experimental medicine and biology · 2022Review
- Article
- Hydralazine and Enzalutamide: Synergistic Partners against Prostate Cancer.Biomedicines · 2021Article
- Insight into the multi-faceted role of the SUV family of H3K9 methyltransferases in carcinogenesis and cancer progression.Biochimica et biophysica acta. Reviews on cancer · 2021Review
- Human equilibrative nucleoside transporter-1 and deoxycytidine kinase can predict gemcitabine effectiveness in Egyptian patients with Hepatocellular carcinoma.Journal of clinical laboratory analysis · 2020Article
- Article
- Histone methyltransferase and drug resistance in cancers.Journal of experimental & clinical cancer research : CR · 2020Review
- Hydralazine Sensitizes to the Antifibrotic Effect of 5-Aza-2'-deoxycytidine in Hepatic Stellate Cells.Biology · 2020Article
- Epidrug Repurposing: Discovering New Faces of Old Acquaintances in Cancer Therapy.Frontiers in oncology · 2020Review
- Role of hepatocyte nuclear factor 4 alpha in cell proliferation and gemcitabine resistance in pancreatic adenocarcinoma.Cancer cell international · 2019Article
Corrections and comments
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Authors and funding
12 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundDown 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
findingsThe 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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