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.
Highlights
Zinc has regulatory and structural functions in a large number of enzymes and transcription factors
The anticancer activity of ML-133 was shown by the NCI hollow fiber assay, a solid tumor efficacy model based on the cell growth of 12 human tumor cell lines encased in biocompatible hollow fibers implanted in mice [25]
ML-133 showed in vivo antitumor activity in a human colon carcinoma (HT-29) xenograft model (Fig. 1C) when it was given p.o. or i.p. into athymic nude mice, with 71% (P = 0.0032) and 69% (P = 0.007) tumor growth inhibition, respectively
Summary
Zinc has regulatory and structural functions in a large number of enzymes and transcription factors. Intracellular zinc homeostasis is regulated by sensor proteins, such as the metal-responsive transcription factor 1, which regulates the transcription of zinc-sensitive genes, including membrane transporter proteins, involved in the cellular and vesicular influx and efflux of zinc, and metallothionein and thionein, which play an important role. Studies of zinc-responsive gene regulation induced by intracellular labile zinc depletion in colon carcinoma HT-29 cells identified Krüppel-like factor 4 (KLF4, known as GKLF) as one of the genes whose expression is most significantly changed (up-regulated) among >10,000 target genes tested [6]. KLFs are members of the SP/XKLF family of transcription factors defined by an amino acid binding domain at the C termini that comprises three C2H2-type zinc fingers with similarity to the developmental gene Krüppel of Drosophila melanogaster [11]. The expression and function of KLFs are relatively tissue restricted [11], with KLF4 mainly expressed in epithelial cells of the gastrointestinal tract, lung, testis, and skin, with a functional role in skin barrier and gastric epithelial homeostasis [13], and development [14]
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