Journal
PHARMACOLOGICAL RESEARCH
Volume 100, Issue -, Pages 255-260Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2015.08.013
Keywords
Polypharmacology; Metastasis; Tumor growth; Resistance; Thiosemicarbazones; DpC
Categories
Funding
- Cancer Institute New South Wales
- Prostate Cancer Foundation of Australia
- National Health and Medical Research Council of Australia (NHMRC)
- NHMRC
- Sydney Medical School Foundation
- AMP Foundation
- Sydney Medical School
- CINSW
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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)/phosphatidylinosito1-3-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. (C) 2015 Elsevier Ltd. All rights reserved.
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