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

• Published in: Pharmacological research Vol. 100; pp. 255 - 260
• Main Authors: Jansson, Patric J., Kalinowski, Danuta S., Lane, Darius J.R., Kovacevic, Zaklina, Seebacher, Nicole A., Fouani, Leyla, Sahni, Sumit, Merlot, Angelica M., Richardson, Des R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01-10-2015
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Down-Regulation - drug effects; DpC; Drug Resistance, Neoplasm - drug effects; Humans; Metastasis; Polypharmacology; PTEN Phosphohydrolase - metabolism; Resistance; Signal Transduction - drug effects; Thiosemicarbazones; Thiosemicarbazones - pharmacology; Thiosemicarbazones - therapeutic use; Tumor growth; Up-Regulation - drug effects; Resistance; Polypharmacology; Metastasis; Tumor growth; Thiosemicarbazones; DpC
• ISSN: 1043-6618; 1096-1186
• DOI: 10.1016/j.phrs.2015.08.013

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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.