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The renaissance of polypharmacology in the development of anti-cancer therapeutics: Inhibition of the "Triad of Death" in cancer by Di-2-pyridylketone thiosemicarbazones.
- Source :
-
Pharmacological research [Pharmacol Res] 2015 Oct; Vol. 100, pp. 255-60. Date of Electronic Publication: 2015 Aug 28. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Down-Regulation drug effects
Humans
PTEN Phosphohydrolase metabolism
Polypharmacology
Proto-Oncogene Mas
Signal Transduction drug effects
Up-Regulation drug effects
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Drug Resistance, Neoplasm drug effects
Thiosemicarbazones pharmacology
Thiosemicarbazones therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1096-1186
- Volume :
- 100
- Database :
- MEDLINE
- Journal :
- Pharmacological research
- Publication Type :
- Academic Journal
- Accession number :
- 26318762
- Full Text :
- https://doi.org/10.1016/j.phrs.2015.08.013