title: The renaissance of polypharmacology in the development of anti-cancer therapeutics: Inhibition of the "Triad of Death" in cancer by Di-2-pyridylketone thiosemicarbazones.
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.
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia. Electronic address: patric.jansson@sydney.edu.au.
authors: Patric J
authors: PJ
authors: Jansson
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia.
authors: Danuta S
authors: DS
authors: Kalinowski
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia.
authors: Darius J R
authors: DJ
authors: Lane
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia.
authors: Zaklina
authors: Z
authors: Kovacevic
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia.
authors: Nicole A
authors: NA
authors: Seebacher
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia.
authors: Leyla
authors: L
authors: Fouani
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia.
authors: Sumit
authors: S
authors: Sahni
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia.
authors: Angelica M
authors: AM
authors: Merlot
authors: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, Blackburn Building (D06), University of Sydney, New South Wales, 2006, Australia. Electronic address: d.richardson@med.usyd.edu.au.
authors: Des R
authors: DR
authors: Richardson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D064798:Polypharmacology; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000187:drug effects; D013882:Thiosemicarbazones / Q000494:pharmacology* / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D013882:Thiosemicarbazones; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: DpC; Metastasis; Polypharmacology; Resistance; Thiosemicarbazones; Tumor growth