Ironing out the role of the cyclin-dependent kinase inhibitor, p21 in cancer: Novel iron chelating agents to target p21 expression and activity.
Moussa RS1, Park KC1, Kovacevic Z1, Richardson DR2.
Free Radic Biol Med. 2018 Mar 20. pii: S0891-5849(18)30130-8. doi: 10.1016/j.freeradbiomed.2018.03.027.
Abstract
Iron (Fe) has become an important target for the development of anti-cancer therapeutics with a number of Fe chelators entering human clinical trials for advanced and resistant cancer. An important aspect of the activity of these compounds is their
multiple molecular targets, including those that play roles in arresting the cell cycle, such as the cyclin-dependent kinase inhibitor, p21. At present, the exact mechanism by which Fe chelators regulate p21 expression remains unclear. However, recent
studies indicate the ability of chelators to up-regulate p21 at the mRNA level was dependent on the chelator and cell-type investigated. Analysis of the p21 promoter identified that the Sp1-3-binding site played a significant role in the activation of
p21 transcription by Fe chelators. Furthermore, there was increased Sp1/ER-α and Sp1/c-Jun complex formation in melanoma cells, suggesting these complexes were involved in p21 promoter activation. Elucidating the mechanisms involved in the regulation of
p21 expression in response to Fe chelator treatment in neoplastic cells will further clarify how these agents achieve their anti-tumor activity. It will also enhance our understanding of the complex roles p21 may play in neoplastic cells and lead to the
development of more effective and specific anti-cancer therapies.

KEYWORDS:
Chemotherapy; Iron chelator; Thiosemicarbazone; p21; p53

PMID: 29572098 DOI: 10.1016/j.freeradbiomed.2018.03.027

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