Synthesis and anticancer properties of water-soluble zinc ionophores.
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 micromol/kg (300 micromol/m(2)) 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.
Magda
Darren
D
Pharmacyclics, Inc, Sunnyvale, California 94085, USA. dmagda@pcyc.com
Lecane
Philip
P
Wang
Zhong
Z
Hu
Weilin
W
Thiemann
Patricia
P
Ma
Xuan
X
Dranchak
Patricia K
PK
Wang
Xiaoming
X
Lynch
Vincent
V
Wei
Wenhao
W
Csokai
Viktor
V
Hacia
Joseph G
JG
Sessler
Jonathan L
JL
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007476:Ionophores / Q000138:chemical synthesis* / Q000627:therapeutic use*; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D020411:Oligonucleotide Array Sequence Analysis; D011725:Pyridines / Q000138:chemical synthesis* / Q000627:therapeutic use*; D012995:Solubility; D008063:Thioctic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D013871:Thiones / Q000138:chemical synthesis* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D014867:Water / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015032:Zinc / Q000032:analysis / Q000378:metabolism*
D000970:Antineoplastic Agents; D007476:Ionophores; D011725:Pyridines; D013871:Thiones; C014047:hydroxypyridines; D014867:Water; C008704:pyrithione; D008063:Thioctic Acid; C015144:dihydrolipoic acid; D015032:Zinc