Synthesis and Anticancer Properties of Water-Soluble Zinc Ionophores
| Autor: | Zhong Wang, Wenhao Wei, Vincent M. Lynch, Xiaoming Wang, Weilin Hu, Patricia Thiemann, Xuan Ma, Philip Lecane, Patricia K. Dranchak, Jonathan L. Sessler, Viktor Csokai, Darren Magda, Joseph G. Hacia |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Cancer Research Cell Survival Pyridines Ionophore chemistry.chemical_element Antineoplastic Agents Zinc Biology Models Biological Article Mice In vivo Neoplasms Gene expression Tumor Cells Cultured Animals Humans Transcription factor Cell Proliferation Oligonucleotide Array Sequence Analysis Ionophores Thioctic Acid Gene Expression Profiling Thiones Water Xenograft Model Antitumor Assays Molecular biology Gene Expression Regulation Neoplastic Heat shock factor Solubility Oncology Biochemistry chemistry Apoptosis Intracellular |
| Zdroj: | Cancer Research. 68:5318-5325 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-08-0601 |
| Popis: | Several water-solubilized versions of the zinc ionophore 1-hydroxypyridine-2-thione (ZnHPT), synthesized as part of the present study, have been found both to increase the intracellular concentrations of free zinc and to produce an antiproliferative activity in exponential phase A549 human lung cancer cultures. Gene expression profiles of A549 cultures treated with one of these water-soluble zinc ionophores, PCI-5002, reveal the activation of stress response pathways under the control of metal-responsive transcription factor 1 (MTF-1), hypoxia-inducible transcription factor 1 (HIF-1), and heat shock transcription factors. Additional oxidative stress response and apoptotic pathways were activated in cultures grown in zinc-supplemented media. We also show that these water-soluble zinc ionophores can be given to mice at 100 μmol/kg (300 μmol/m2) with no observable toxicity and inhibit the growth of A549 lung and PC3 prostate cancer cells grown in xenograft models. Gene expression profiles of tumor specimens harvested from mice 4 h after treatment confirmed the in vivo activation of MTF-1–responsive genes. Overall, we propose that water-solubilized zinc ionophores represent a potential new class of anticancer agents. [Cancer Res 2008;68(13):5318–25] |
| Databáze: | OpenAIRE |
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