Iron Transport

Re: symposium 473 Kicic/Baker

On Thu Dec 10, Doug Templeton wrote
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>Hello Anthony. The MTT assay should give results proportional to cell number if viability is
>equivalent. Have you checked viability or cell number by any independent means? Also, I believe
>one of the major enzymes involved in MTT reduction is mitochondrial succinate dehydrogenase.
> This is an Fe-containing enzyme that can be inhibited by Fe chelators. I wonder if in part your
>results reflect accessibility of the chelator to this enzyme?

>Doug Templeton

Hi Doug,

Thank you for your thoughtful comments on this work. There is of course good agreement between our controls with regard to cell numbers and MTT levels. Of the chelators in our study so far we have only compared cell number with MTT results for PIH, for which there is good agreement. We will certainly assess the other chelators using the two approaches. However, in other studies using this procedure to look at other chelators (eg see 1 and 2) a good correlation was found between cell number and MTT levels.

With regard to your second point, certainly results we get could in part reflect access of the chelators to mitochondrial succinate dehydrogenase, and this could explain the low antiproliferative effect of EDTA and BPS. However the story is more complex. For example, the most active antiproliferative agent was the highly impermeable chelator DTPA, and the water soluble DFO was consistently more effective than the lipophilic PIH. Presumably chelators with different size, lipophilicity and Fe binding affinity may act on different cellular sites for Fe, often with the same end result of disruption of cellular Fe metabolism and cell growth

1. Richardson, D.R., Tran, E., and Ponka, P (1995) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents. Blood 86: 4295-4306.

2. Torti, S.V., Torti, F.M., Whitman, S.P., Brechbiel, M.W., Park, G., Planalp, R.P. (1998) Tumor cell cytotoxicity of a novel metal chelator. Blood 92: 1384-1389.

Anthony Kicic

Tue Dec 15