Hybrid topoisomerase I and HDAC inhibitors as dual action anticancer agents

PLoS One. 2018 Oct 9;13(10):e0205018. doi: 10.1371/journal.pone.0205018. eCollection 2018.

Abstract

Recent studies have shown that HDAC inhibitors act synergistically with camptothecin derivatives in combination therapies. To exploit this synergy, new hybrid molecules targeting simultaneously topoisomerase I and HDAC were designed. In particular, a selected multivalent agent containing a camptothecin and a SAHA-like template showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Binding Sites
  • Camptothecin / chemistry
  • Camptothecin / pharmacology
  • Camptothecin / therapeutic use
  • Catalytic Domain
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Topoisomerases, Type I / chemistry
  • DNA Topoisomerases, Type I / metabolism
  • Female
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Mice
  • Mice, Nude
  • Molecular Dynamics Simulation
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology
  • Topoisomerase I Inhibitors / therapeutic use*
  • Transplantation, Heterologous

Substances

  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Topoisomerase I Inhibitors
  • DNA Topoisomerases, Type I
  • Camptothecin

Grants and funding

The authors received no specific funding for this work. Scientia Advice provided support in the form of salaries for author RA, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section.