A novel small molecule with potent anticancer activity inhibits cell growth by modulating intracellular labile zinc homeostasis.

Abstract

ML-133 is a novel small molecule with potent antiproliferative activity, as shown in cancer cell lines and in a human colon tumor xenograft model. ML-133 reduces the concentration of intracellular labile zinc in HT-29 colon cancer cells, leading to induction of the Krüppel-like factor 4 transcription factor. Krüppel-like factor 4 displaces the positive regulator SP1 from the cyclin D1 promoter, thereby negatively regulating the expression of cyclin D1 and promoting the G(1)-S phase arrest of cell proliferation. The antiproliferative and antitumor activity of ML-133 described in the present study suggests modulation of intracellular zinc homeostasis as a potential strategy for the treatment of several cancer types, and ML-133 represents a promising new class of antitumor agents that deserves further development.

• Authors: Mario Huesca, Lisa S Lock, Aye Aye Khine, Stéphane Viau, Robert Peralta, I Howard Cukier, Hongnan Jin, Raed A Al-Qawasmeh, Yoon Lee, Jim Wright, Aiping Young
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 9 Pg. 2586-96 (Sep 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19755513 (Publication Type: Journal Article)

Chemical References

• 2-(2-methyl-1H-indol-3-yl)-1H-imidazol(4,5-f)(1,10)phenanthroline
• Antineoplastic Agents
• DNA Primers
• Imidazoles
• KLF4 protein, human
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Phenanthrolines
• Sp1 Transcription Factor
• Cyclin D1
• Zinc

Topics

• Antineoplastic Agents (pharmacology)
• Base Sequence
• Blotting, Western
• Cell Cycle
• Cell Division (drug effects)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (metabolism, pathology)
• Cyclin D1 (genetics)
• DNA Primers
• Electrophoresis, Polyacrylamide Gel
• Flow Cytometry
• HT29 Cells
• Homeostasis (drug effects)
• Humans
• Imidazoles (pharmacology)
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (biosynthesis)
• Phenanthrolines (pharmacology)
• Polymerase Chain Reaction
• Promoter Regions, Genetic
• Sp1 Transcription Factor (metabolism)
• Up-Regulation (drug effects)
• Zinc (metabolism)