Novel epigenetic target therapy for prostate cancer: a preclinical study

PLoS One. 2014 May 22;9(5):e98101. doi: 10.1371/journal.pone.0098101. eCollection 2014.

Abstract

Epigenetic events are critical contributors to the pathogenesis of cancer, and targeting epigenetic mechanisms represents a novel strategy in anticancer therapy. Classic demethylating agents, such as 5-Aza-2'-deoxycytidine (Decitabine), hold the potential for reprograming somatic cancer cells demonstrating high therapeutic efficacy in haematological malignancies. On the other hand, epigenetic treatment of solid tumours often gives rise to undesired cytotoxic side effects. Appropriate delivery systems able to enrich Decitabine at the site of action and improve its bioavailability would reduce the incidence of toxicity on healthy tissues. In this work we provide preclinical evidences of a safe, versatile and efficient targeted epigenetic therapy to treat hormone sensitive (LNCap) and hormone refractory (DU145) prostate cancers. A novel Decitabine formulation, based on the use of engineered erythrocyte (Erythro-Magneto-Hemagglutinin Virosomes, EMHVs) drug delivery system (DDS) carrying this drug, has been refined. Inside the EMHVs, the drug was shielded from the environment and phosphorylated in its active form. The novel magnetic EMHV DDS, endowed with fusogenic protein, improved the stability of the carried drug and exhibited a high efficiency in confining its delivery at the site of action in vivo by applying an external static magnetic field. Here we show that Decitabine loaded into EMHVs induces a significant tumour mass reduction in prostate cancer xenograft models at a concentration, which is seven hundred times lower than the therapeutic dose, suggesting an improved pharmacokinetics/pharmacodynamics of drug. These results are relevant for and discussed in light of developing personalised autologous therapies and innovative clinical approach for the treatment of solid tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / therapeutic use
  • Azacitidine / analogs & derivatives
  • Azacitidine / therapeutic use
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Decitabine
  • Epigenesis, Genetic*
  • Humans
  • Male
  • Mass Spectrometry
  • Mice
  • Mice, Inbred BALB C
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics

Substances

  • Antimetabolites, Antineoplastic
  • Decitabine
  • Azacitidine

Grants and funding

This work was supported by Consiglio Nazionale delle Ricerche (CNR) funding and by European Community funding for POR CReO FESR 2007-2013, BANDO UNICO R&S-ANNO 2012 of Regione Toscana-Project acronym Title: ACTILA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.