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Human thioredoxin reductase is efficiently inhibited by (2,2':6',2' '-terpyridine)platinum(II) complexes. Possible
K Becker1, C Herold-Mende, J J Park
1Interdisciplinary Research Center, Giessen University, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany. becker.katja@gmx.de
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 K(i) for the competitive component of the inhibition is 4 nM and the IC(50) 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 microM 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 microM 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 targets-hTrxR and DNA-as antitumor agents is discussed.
Insights
New platinum complexes show promise against glioblastoma. These compounds target thioredoxin reductase (TrxR), a key enzyme, and DNA, inhibiting cancer cell growth effectively.
Area of Science:
- Oncology
- Medicinal Chemistry
- Biochemistry
Background:
- Pediatric brain tumors, particularly glioblastoma multiforme, have a poor prognosis with limited treatment options.
- Platinum(II) complexes with (2,2 ':6 ',2"-terpyridine) ligands exhibit DNA-intercalating properties and potential as chemotherapeutic agents.
Purpose of the Study:
- To identify the molecular targets of (2,2 ':6 ',2"-terpyridine)platinum(II) complexes.
- To synthesize novel platinum complexes for optimized inhibition of identified targets.
- To evaluate the efficacy of these complexes against glioblastoma and head-and-neck squamous carcinoma cell lines.
Main Methods:
- Enzyme inhibition assays were performed using purified human thioredoxin reductase (hTrxR) and glutathione reductase.
- Synthesis and characterization of novel (2,2 ':6 ',2"-terpyridine)platinum(II) complexes.
- Cell proliferation assays on glioblastoma and head-and-neck squamous carcinoma cell lines.
- Intracellular enzyme activity measurements post-treatment.
Main Results:
- The selenoenzyme thioredoxin reductase (TrxR) was identified as a primary target of the platinum complexes.
- The most potent inhibitor, N,S-bis(2,2 ':6 ',2"-terpyridine)platinum(II)-thioacetimine trinitrate, demonstrated potent competitive (K(i) = 4 nM) and tight-binding (IC(50) = 2 nM) inhibition of hTrxR.
- Glutathione reductase was significantly less affected (>1000-fold difference).
- The complexes effectively inhibited proliferation in glioblastoma and head-and-neck squamous carcinoma cell lines.
- In glioblastoma cells, treatment led to initial hTrxR activity decrease followed by recovery in surviving cells, with sustained inhibition of hTrxR but not glutathione reductase.
Conclusions:
- (2,2 ':6 ',2"-terpyridine)platinum(II) complexes exhibit potent antitumor activity by targeting both hTrxR and DNA.
- These complexes represent a promising new class of chemotherapeutic agents for glioblastoma and other cancers.
- Selective inhibition of hTrxR over glutathione reductase may contribute to their therapeutic potential.