Opening Remarks

2 February 2004

Henry Fliss

Therapeutic potential of induced intracellular zinc transients

Zinc as an intracellular signaling agent is a concept whose time has finally arrived. In addition to the work of Bird at al. (1) and Korichneva et al., (2), cited in Dr. Adler’s opening remarks, other studies such as Smith et al. (3) and Sauer et al. (4) strongly suggest that intracellular zinc transients or fluxes have a pronounced regulatory effect on cell growth and apoptosis.

Our own studies tend to support this concept. We have shown that physiological oxidants can cause the release of intracellular zinc (5-7), and that this release transiently increases the intracellular “free” zinc concentration from roughly 200 pM to approximately 7 nM (8).

Proceeding on the assumption that such zinc transients represent an intracellular signaling mechanism, we examined the possibility that the induction of artificial zinc transients in cells could trigger regulatory effects. Specifically, we examined the ability of zinc ionophores to block the apoptotic machinery in injured tissues. In a recent abstract, we describe the ability of very low doses of zinc ionophores such as zinc- pyrithione and zinc-diethyldithiocarbamate to block apoptosis and improve function in animal models of myocardial infarction and stroke (9).

We are currently continuing these promising studies in the setting of a new biotech company, Zinc Therapeutics, Inc. We believe that, much like calcium transients, zinc transients act as a signaling “language” to trigger intracellular events. We anticipate that, once the words of this language are deciphered, we will be able to “speak” to the cell using zinc ionophores.

I am hoping to initiate a discussion of this important therapeutic question. One question that may be of particular interest is:

How can one identify the target(s) of zinc transients given that hundreds of metalloproteins are known to interact with zinc?

Reference List

1. Bird,A.J., McCall,K., Kramer,M., Blankman,E., Winge,D.R., and Eide,D.J. 2003. Zinc fingers can act as Zn²⁺ sensors to regulate transcriptional activation domain function. EMBO J.22:5137-5146. [Abstract]

2. Korichneva,I., Hoyos,B., Chua,R., Levi,E., and Hammerling,U. 2002. Zinc Release from Protein Kinase C as the Common Event during Activation by Lipid Second Messenger or Reactive Oxygen. J.Biol.Chem. 277:44327-44331. [Abstract]

3. Smith,P.J., Wiltshire,M., Davies,S., Chin,S.F., Campbell,A.K., and Errington,R.J. 2002. DNA damage-induced [Zn²⁺]_i transients: correlation with cell cycle arrest and apoptosis in lymphoma cells. Am.J.Physiol. 283:C609-C622. [Abstract]

4. Sauer,G.R., Smith,D.M., Cahalane,M., Wu,L.N., and Wuthier,R.E. 2003. Intracellular zinc fluxes associated with apoptosis in growth plate chondrocytes. J.Cell.Biochem. 88:954-969.

5. Fliss,H. and Ménard,M. 1992. Oxidant-induced mobilization of zinc from metallothionein. Arch.Biochem.Biophys. 293:195-199.

6. Fliss,H., Ménard,M., and Desai,M. 1991. Hypochlorous acid mobilizes cellular zinc. Can.J.Physiol.Pharmacol. 69:1686-1691.

7. Tatsumi,T. and Fliss,H. 1994. Hypochlorous acid mobilizes intracellular zinc in isolated rat heart myocytes. J.Mol.Cell.Cardiol. 26:471-479.

8. Turan,B., Fliss,H., and Désilets,M. 1997. Oxidants increase intracellular free Zn²⁺ concentration in rabbit ventricular myocytes. Am.J.Physiol. 272:H2095-H2106. [Abstract]

9. Gulyaeva,N., Stepanichev,M., Onufriev,M., Lazareva,N., and Fliss,H. 2003. Zinc ionophores as neuroprotective agents. J.Neurochem. 85 Suppl.2:27 (Abstr.)