title: 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.affiliation: Lorus Therapeutics Inc., Toronto, Ontario M9W 4Z7 Canada. mhuesca@lorusthera.com
authors.forename: Mario
authors.initials: M
authors.lastname: Huesca
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Lock
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Khine
authors.forename: Stéphane
authors.initials: S
authors.lastname: Viau
authors.forename: Robert
authors.initials: R
authors.lastname: Peralta
authors.forename: I Howard
authors.initials: IH
authors.lastname: Cukier
authors.forename: Hongnan
authors.initials: H
authors.lastname: Jin
authors.forename: Raed A
authors.initials: RA
authors.lastname: Al-Qawasmeh
authors.forename: Yoon
authors.initials: Y
authors.lastname: Lee
authors.forename: Jim
authors.initials: J
authors.lastname: Wright
authors.forename: Aiping
authors.initials: A
authors.lastname: Young
mesh_terms: 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*
chemical_list: 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