A novel small molecule with potent anticancer activity inhibits cell growth by modulating intracellular labile zinc homeostasis.
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.
Huesca
Mario
M
Lorus Therapeutics Inc., Toronto, Ontario M9W 4Z7 Canada. mhuesca@lorusthera.com
Lock
Lisa S
LS
Khine
Aye Aye
AA
Viau
Stéphane
S
Peralta
Robert
R
Cukier
I Howard
IH
Jin
Hongnan
H
Al-Qawasmeh
Raed A
RA
Lee
Yoon
Y
Wright
Jim
J
Young
Aiping
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D015153:Blotting, Western; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D019073:HT29 Cells; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis; D010618:Phenanthrolines / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D015032:Zinc / Q000378:metabolism*
C546026:2-(2-methyl-1H-indol-3-yl)-1H-imidazol(4,5-f)(1,10)phenanthroline; D000970:Antineoplastic Agents; D017931:DNA Primers; D007093:Imidazoles; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D010618:Phenanthrolines; D016329:Sp1 Transcription Factor; D019938:Cyclin D1; D015032:Zinc