Synthesis and Anticancer Properties of Water-soluble Zinc Ionophores

Overview

Journal Cancer Res

Specialty Oncology

Date 2008 Jul 3

PMID 18593933

Citations 35

Authors

Darren Magda

Philip Lecane

Zhong Wang

Weilin Hu

Patricia Thiemann

Xuan Ma

Patricia K Dranchak

Xiaoming Wang

Vincent Lynch

Wenhao Wei

Viktor Csokai

Joseph G Hacia

Jonathan L Sessler

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Decoding the Implications of Zinc in the Development and Therapy of Leukemia.

Zhu B, Yang C, Hua S, Li K, Shang P, Li Z Adv Sci (Weinh). 2025; 12(9):e2412225.

PMID: 39887881 PMC: 11884550. DOI: 10.1002/advs.202412225.

MTF1 genetic variants are associated with lung cancer risk in the Chinese Han population.

Cheng Y, Zhang C, Li Q, Yang X, Chen W, He K BMC Cancer. 2024; 24(1):778.

PMID: 38943058 PMC: 11212402. DOI: 10.1186/s12885-024-12516-y.

Coupling Photoresponsive Transmembrane Ion Transport with Transition Metal Catalysis.

Chao X, Johnson T, Temian M, Docker A, Wallabregue A, Scott A J Am Chem Soc. 2024; 146(7):4351-4356.

PMID: 38334376 PMC: 10885138. DOI: 10.1021/jacs.3c13801.

Induced Zinc Loss Produces Heterogenous Biological Responses in Melanoma Cells.

Rudolf E, Rudolf K Int J Mol Sci. 2022; 23(15).

PMID: 35955445 PMC: 9368258. DOI: 10.3390/ijms23158312.

Zinc pyrithione is a potent inhibitor of PL and cathepsin L enzymes with inhibition of SARS-CoV-2 entry and replication.

Kladnik J, Dolinar A, Kljun J, Perea D, Grau-Exposito J, Genesca M J Enzyme Inhib Med Chem. 2022; 37(1):2158-2168.

PMID: 35943189 PMC: 9367663. DOI: 10.1080/14756366.2022.2108417.

References

Semenza G . Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3(10):721-32. DOI: 10.1038/nrc1187. View

Feng P, Li T, Guan Z, Franklin R, Costello L . Effect of zinc on prostatic tumorigenicity in nude mice. Ann N Y Acad Sci. 2004; 1010:316-20. DOI: 10.1196/annals.1299.056. View

Jasim S, Tjalve H . Effects of sodium pyridinethione on the uptake and distribution of nickel, cadmium and zinc in pregnant and non-pregnant mice. Toxicology. 1986; 38(3):327-50. DOI: 10.1016/0300-483x(86)90148-4. View

Schofield C, Ratcliffe P . Oxygen sensing by HIF hydroxylases. Nat Rev Mol Cell Biol. 2004; 5(5):343-54. DOI: 10.1038/nrm1366. View

Jasim S, Tjalve H . Effect of zinc pyridinethione on the tissue disposition of nickel and cadmium in mice. Acta Pharmacol Toxicol (Copenh). 1986; 59(3):204-8. DOI: 10.1111/j.1600-0773.1986.tb00155.x. View

Zhang B, Kirov S, Snoddy J . WebGestalt: an integrated system for exploring gene sets in various biological contexts. Nucleic Acids Res. 2005; 33(Web Server issue):W741-8. PMC: 1160236. DOI: 10.1093/nar/gki475. View

Choi J, Kim T, Kim S, Baek S, Kim J, Lee S . Overexpression of mitochondrial thioredoxin reductase and peroxiredoxin III in hepatocellular carcinomas. Anticancer Res. 2003; 22(6A):3331-5. View

Gibson W, Chamberlain M, Parsons J, Brunskill J, Leftwich D, Lock S . The effect and mode of action of zinc pyrithione on cell growth. I. In vitro studies. Food Chem Toxicol. 1985; 23(1):93-102. DOI: 10.1016/0278-6915(85)90226-1. View

Wang Z, Lecane P, Thiemann P, Fan Q, Cortez C, Ma X . Synthesis and biologic properties of hydrophilic sapphyrins, a new class of tumor-selective inhibitors of gene expression. Mol Cancer. 2007; 6:9. PMC: 1784109. DOI: 10.1186/1476-4598-6-9. View

10.

Lecane P, Karaman M, Sirisawad M, Naumovski L, Miller R, Hacia J . Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005; 65(24):11676-88. DOI: 10.1158/0008-5472.CAN-05-2754. View

11.

Hirsila M, Koivunen P, Xu L, Seeley T, Kivirikko K, Myllyharju J . Effect of desferrioxamine and metals on the hydroxylases in the oxygen sensing pathway. FASEB J. 2005; 19(10):1308-10. DOI: 10.1096/fj.04-3399fje. View

12.

Smart D, Ortiz K, Mattson D, Bradbury C, Bisht K, Sieck L . Thioredoxin reductase as a potential molecular target for anticancer agents that induce oxidative stress. Cancer Res. 2004; 64(18):6716-24. DOI: 10.1158/0008-5472.CAN-03-3990. View

13.

Magda D, Lecane P, Miller R, Lepp C, Miles D, Mesfin M . Motexafin gadolinium disrupts zinc metabolism in human cancer cell lines. Cancer Res. 2005; 65(9):3837-45. DOI: 10.1158/0008-5472.CAN-04-4099. View

14.

Jeffcoat A, GIBSON W, Rodriguez P, Turan T, Hughes P, Twine M . Zinc pyridinethione: urinary metabolites of zinc pyridinethione in rabbits, rats, monkeys, and dogs after oral dosing. Toxicol Appl Pharmacol. 1980; 56(1):141-54. DOI: 10.1016/0041-008x(80)90139-8. View

15.

Gee K, Zhou Z, Sensi S, Weiss J . Measuring zinc in living cells. A new generation of sensitive and selective fluorescent probes. Cell Calcium. 2002; 31(5):245-51. DOI: 10.1016/S0143-4160(02)00053-2. View

16.

Kirkpatrick D, Kuperus M, Dowdeswell M, Potier N, Donald L, Kunkel M . Mechanisms of inhibition of the thioredoxin growth factor system by antitumor 2-imidazolyl disulfides. Biochem Pharmacol. 1998; 55(7):987-94. DOI: 10.1016/s0006-2952(97)00597-2. View

17.

Mehta M, Rodrigus P, Terhaard C, Rao A, Suh J, Roa W . Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol. 2003; 21(13):2529-36. DOI: 10.1200/JCO.2003.12.122. View

18.

Costello L, Franklin R . Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer. Prostate. 1998; 35(4):285-96. DOI: 10.1002/(sici)1097-0045(19980601)35:4<285::aid-pros8>3.0.co;2-f. View

19.

Sirotnak F, Zakowski M, Miller V, Scher H, Kris M . Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res. 2001; 6(12):4885-92. View

20.

GIBSON W, Jeffcoat A, Turan T, Wendt R, Hughes P, Twine M . Zinc pyridinethione: serum metabolites of zinc pyridinethione in rabbits, rats, monkeys, and dogs after oral dosing. Toxicol Appl Pharmacol. 1982; 62(2):237-50. DOI: 10.1016/0041-008x(82)90122-3. View