Photoactivatable, mitochondria targeting dppz iridium(III) complex selectively interacts and damages mitochondrial DNA in cancer cells
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F24%3A00585258" target="_blank" >RIV/68081707:_____/24:00585258 - isvavai.cz</a>
Alternative codes found
RIV/61989592:15310/24:73626585
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S000927972400067X?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S000927972400067X?via%3Dihub</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.cbi.2024.110921" target="_blank" >10.1016/j.cbi.2024.110921</a>
Alternative languages
Result language
angličtina
Original language name
Photoactivatable, mitochondria targeting dppz iridium(III) complex selectively interacts and damages mitochondrial DNA in cancer cells
Original language description
Cyclometalated Ir(III) complex [Ir(L)2(dppz)]PF6 (where L = 1-methyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole and dppz = dipyrido [3,2-a:2 ',3 '-c]phenazine) (Ir1) is potent anticancer agent whose potency can be significantly increased by irradiation with blue light. Structural features of the cyclometalated Ir(III) complex Ir1 investigated in this work, particularly the presence of dppz ligand possessing an extended planar area, suggest that this complex could interact with DNA. Here, we have shown that Ir1 accumulates predominantly in mitochondria of cancer cells where effectively and selectively binds mitochondrial (mt)DNA. Additionally, the results demonstrated that Ir1 effectively suppresses transcription of mitochondria-encoded genes, especially after irradiation, which may further affect mitochondrial (and thus also cellular) functions. The observation that Ir1 binds selectively to mtDNA implies that the mechanism of its biological activity in cancer cells may also be connected with its interaction and damage to mtDNA. Further investigations revealed that Ir1 tightly binds DNA in a cellfree environment, with sequence preference for GC over AT base pairs. Although the dppz ligand itself or as a ligand in structurally similar DNA-intercalating Ru polypyridine complexes based on dppz ligand intercalates into DNA, the DNA binding mode of Ir1 comprises surprisingly a groove binding rather than an intercalation. Also interestingly, after irradiation with visible (blue) light, Ir1 was capable of cleaving DNA, likely due to the production of superoxide anion radical. The results of this study show that mtDNA damage by Ir1 plays a significant role in its mechanism of antitumor efficacy. In addition, the results of this work are consistent with the hypothesis and support the view that targeting the mitochondrial genome is an effective strategy for anticancer (photo)therapy and that the class of photoactivatable dipyridophenazine Ir(III) compounds may represent prospective substances suitable for further testing.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/GA23-06307S" target="_blank" >GA23-06307S: Metal-based compounds as candidates for antimetastatic chemotherapy</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Chemico-Biological Interactions
ISSN
0009-2797
e-ISSN
1872-7786
Volume of the periodical
392
Issue of the periodical within the volume
FEB 2024
Country of publishing house
IE - IRELAND
Number of pages
9
Pages from-to
110921
UT code for WoS article
001197006000001
EID of the result in the Scopus database
2-s2.0-85186762159