The renaissance of polypharmacology in the development of anti-cancer therapeutics: Inhibition of the 鈥淭riad of Death鈥?in cancer by Di-2-pyridylketone thiosemicarbazones

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• 作者：Patric J. Jansson¹ ; ^{patric.jansson@sydney.edu.au" class="auth_mail" title="E-mail the corresponding author} ; Danuta S. Kalinowski ; Darius J.R. Lane ; Zaklina Kovacevic ; Nicole A. Seebacher ; Leyla Fouani ; Sumit Sahni ; Angelica M. Merlot ; Des R. Richardson¹ ; ^{d.richardson@med.usyd.edu.au" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Polypharmacology ; Metastasis ; Tumor growth ; Resistance ; Thiosemicarbazones ; DpC
• 刊名：Pharmacological Research
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：100
• 期：Complete
• 页码：255-260
• 全文大小：1198 K

文摘

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.