The renaissance of polypharmacology in the development of anti-cancer therapeutics: Inhibition of the "Triad of Death" in cancer by Di-2-pyridylketone thiosemicarbazones

Pharmacol Res. 2015 Oct:100:255-60. doi: 10.1016/j.phrs.2015.08.013. Epub 2015 Aug 28.

Abstract

Cancer is a disease that is a "moving target", since as the condition progresses, the molecular targets change and evolve. Moreover, due to clonal selection, a specific anti-cancer drug with one molecular target may only be effective for a limited time period before drug resistance results and the agent becomes ineffective. Hence, the concept of an anti-tumor therapeutic exhibiting polypharmacology can be highly advantageous, rather than a therapeutic obstacle. A novel class of agents possessing these desirable properties are the di-2-pyridylketone thiosemicarbazones, which bind iron and copper to affect a variety of critical molecular targets in tumors. In fact, these compounds possess multiple properties that enable them to overcome the "triad of death" in cancer, namely: primary tumor growth, drug resistance and metastasis. In fact, at the molecular level, their potent anti-oncogenic activity includes: up-regulation of the metastasis suppressor, N-myc downstream regulated gene 1; up-regulation of the tumor suppressor, PTEN; down-regulation of the proto-oncogene, cyclin D1; inhibition of the rate-limiting step in DNA synthesis catalyzed by ribonucleotide reductase; and the inhibition of multiple oncogenic signaling pathways, e.g., Ras/MAPK signaling, protein kinase B (AKT)/phosphatidylinositol-3-kinase, ROCK/pMLC2, etc. This Perspective article discusses the advantages of incorporating polypharmacology into anti-cancer drug design using the di-2-pyridylketone thiosemicarbazones as a pertinent example.

Keywords: DpC; Metastasis; Polypharmacology; Resistance; Thiosemicarbazones; Tumor growth.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use*
  • Down-Regulation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Humans
  • PTEN Phosphohydrolase / metabolism
  • Polypharmacology
  • Proto-Oncogene Mas
  • Signal Transduction / drug effects
  • Thiosemicarbazones / pharmacology*
  • Thiosemicarbazones / therapeutic use*
  • Up-Regulation / drug effects

Substances

  • Antineoplastic Agents
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Thiosemicarbazones
  • PTEN Phosphohydrolase
  • PTEN protein, human