Anticancer dinuclear Ir(III) complex activates Nrf2 and interferes with NAD(H) in cancer cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F25%3A73625679" target="_blank" >RIV/61989592:15310/25:73625679 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0162013424002289" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0162013424002289</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jinorgbio.2024.112704" target="_blank" >10.1016/j.jinorgbio.2024.112704</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Anticancer dinuclear Ir(III) complex activates Nrf2 and interferes with NAD(H) in cancer cells

Popis výsledku v původním jazyce

Dinuclear complex [Ir2(μ-L1)(η5-Cp*)2Cl2](PF6)2 (1) exhibits low micromolar cytotoxic activity in vitro in various human cancer cells (GI50 = 1.7–3.0 μM) and outperformed its mononuclear analogue [Ir(η5-Cp*)Cl(L2)]PF6 (2; GI50 &gt; 40.0 μM); Cp* = pentamethylcyclopentadienyl, L1 = 4-chloro-2,6-bis[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl]pyridine, L2 = 5-(pyridin-2-yl)-1,3,4-thiadiazol-2-amine. Compound 1 upregulated the Keap1/Nrf2 oxidative stress-protective pathway in the treated MV4–11 acute myeloid leukemia cells. In connection with the redox-mediated mode of action of 1, its NADH-oxidizing activity was detected in solution (1H NMR), while NAD+ remained intact (with formate as a hydride source). Surprisingly, only negligible NADH oxidation was detected in the presence of the reduced glutathione and ascorbate. Following the results of in-solution experiments, NAD(H) concentration was assessed in 1-treated MV4–11 cancer cells. Besides the intracellular NADH oxidation in the presence of 1, the induced oxidative stress also led to a decrease of NAD+, resulting in depletion of both NAD+/NADH coenzymes. The discussed findings provide new insight into the biochemical effects of catalytic anticancer compounds that induce cell death via a redox-mediated mode of action.

Název v anglickém jazyce

Anticancer dinuclear Ir(III) complex activates Nrf2 and interferes with NAD(H) in cancer cells

Popis výsledku anglicky

Dinuclear complex [Ir2(μ-L1)(η5-Cp*)2Cl2](PF6)2 (1) exhibits low micromolar cytotoxic activity in vitro in various human cancer cells (GI50 = 1.7–3.0 μM) and outperformed its mononuclear analogue [Ir(η5-Cp*)Cl(L2)]PF6 (2; GI50 &gt; 40.0 μM); Cp* = pentamethylcyclopentadienyl, L1 = 4-chloro-2,6-bis[5-(pyridin-2-yl)-1,3,4-thiadiazol-2-yl]pyridine, L2 = 5-(pyridin-2-yl)-1,3,4-thiadiazol-2-amine. Compound 1 upregulated the Keap1/Nrf2 oxidative stress-protective pathway in the treated MV4–11 acute myeloid leukemia cells. In connection with the redox-mediated mode of action of 1, its NADH-oxidizing activity was detected in solution (1H NMR), while NAD+ remained intact (with formate as a hydride source). Surprisingly, only negligible NADH oxidation was detected in the presence of the reduced glutathione and ascorbate. Following the results of in-solution experiments, NAD(H) concentration was assessed in 1-treated MV4–11 cancer cells. Besides the intracellular NADH oxidation in the presence of 1, the induced oxidative stress also led to a decrease of NAD+, resulting in depletion of both NAD+/NADH coenzymes. The discussed findings provide new insight into the biochemical effects of catalytic anticancer compounds that induce cell death via a redox-mediated mode of action.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10402 - Inorganic and nuclear chemistry

Projekt

<a href="/cs/project/NU22-08-00236" target="_blank" >NU22-08-00236: Preklinické studie neplatinových metaloléčiv v terapii rakoviny plic</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

JOURNAL OF INORGANIC BIOCHEMISTRY

ISSN

0162-0134

e-ISSN

1873-3344

Svazek periodika

262

Číslo periodika v rámci svazku

JAN

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

9

Strana od-do

"12704-1"-"112704-9"

Kód UT WoS článku

001334089500001

EID výsledku v databázi Scopus

2-s2.0-85203236951