Human Thioredoxin Reductase Is Efficiently Inhibited by (2,2‘:6‘,2‘ ‘-Terpyridine)platinum(II) Complexes. Possible Implications for a Novel Antitumor Strategy

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Abstract
Malignant neoplasms of the brain represent the second leading cause of cancer-related mortality in children under the age of 15. The prognosis of patients with glioblastoma multiforme, the most malignant type of gliomas, remains poor offering a median survival time of only 1 year. (2,2‘:6‘,2‘ ‘-Terpyridine)platinum(II) complexes are known to possess DNA-intercalating activity and have been shown to be potential chemotherapeutic agents. In the present study we identified the selenoenzyme thioredoxin reductase (TrxR) as a major target of (2,2‘:6‘,2‘ ‘-terpyridine)platinum(II) complexes. New complexes were synthesized in order to optimize this inhibition. The NADPH-reduced enzyme is inhibited almost stoichiometrically by the complexes involving a reversible competitive and an irreversible tight-binding component. For the most potent inhibitor, N,S-bis(2,2‘:6‘,2‘ ‘-terpyridine)platinum(II)-thioacetimine trinitrate, the Ki for the competitive component of the inhibition is 4 nM and the IC50 for the tight-binding component is 2 nM after an incubation time of 5 min. The closely related but non-selenium-containing enzyme glutathione reductase is much less inhibited (by a factor of >1000). The platinum complexes were found to strongly inhibit the proliferation of three different glioblastoma cell lines as well as of two different head-and-neck squamous carcinoma cell lines. In a glioblastoma cell culture, less than 10 μM of a platinum(II) compound caused an initial drop of hTrxR activity which was followed by an increase of activity in the surviving cells. A 10 μM inhibitor added every 24 h led to 4% residual hTrxR activity but 100% glutathione reductase activity in the cells surviving for 67 h. The potential of (2,2‘:6‘,2‘ ‘-terpyridine)platinum(II) complexes acting simultaneously at two different intracellular targetshTrxR and DNAas antitumor agents is discussed.

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