Preventive Effect of Trimidox on Oxidative Stress in U937 Cell Line

Kanno, Syu‐ichi; Kakuta, Mai; Kitajima, Yasue; Osanai, Yuu; Kurauchi, Kaori; Ohtake, Takaharu; Ujibe, Mayuko; Uwai, Kouji; Takeshita, Mitsuhiro; Ishikawa, Masaaki

doi:10.1248/bpb.30.994

Cited by 7 publications

(5 citation statements)

References 23 publications

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“…On contrary, DID can be described to possess sensitizing role for DOX-induced cytotoxicity in CRC cells. This might be similar to the effect of trimidox, another ribonuclueotide reductase inhibitor, which exhibits both anticancer and potent antioxidant properties57. DID is known to be a ribonucleotide reductase enzyme inhibitor which might partly explain its anti-proliferative and chemosensitizing effects33.…”

Section: Discussionmentioning

confidence: 87%

Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Khaleel

Al‐Abd

Ali

et al. 2016

Sci Rep

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Doxorubicin (DOX) has limited efficacy in colorectal cancer due to multi-drug resistance. Resveratrol (RES) and didox (DID) are polyhydroxyphenols with potential chemosensitizing effects. Herein, we assessed the chemomodulatory effects of RES and DID to DOX in colorectal cancer cells. Equitoxic combination of DOX with RES and DID in HCT 116 reduced the IC50 of DOX from 0.96 ± 0.02 μM to 0.52 ± 0.05 μM and 0.4 ± 0.06 μM, respectively. Similarly, combination of DOX with RES and DID in HT-29 decreased the IC50’s of DOX from 0.88 ± 0.03 μM to 0.47 ± 0.02 μM and 0.29 ± 0.04 μM, respectively. The expressions of p53 and Bax genes were markedly elevated in HCT 116 cells after exposure to DOX/DID. In HT-29 cells, the expression of Bcl-XL gene was significantly decreased after exposure to DOX/DID. In addition, combination of DOX with RES significantly increased the expression of Bax gene in HCT 116 cells. RES treatment induced significant S-phase arrest in DOX-treated HCT 116 cells, while DID induced G2/M- and S-phase arrest in HCT 116 and HT-29, respectively. Both RES and DID significantly enhanced the intracellular entrapment of DOX due to blocking the efflux activity of p-glycoprotein pump. In conclusion, RES and DID sensitize colorectal cancer cells to DOX via facilitating apoptosis and enhancing intracellular entrapment of DOX.

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Section: Discussionmentioning

confidence: 87%

Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Khaleel

Al‐Abd

Ali

et al. 2016

Sci Rep

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“…Several RR inhibitors including HU [27], DFO [27], resveratrol [26], and trimidox [28] are all known to scavenge diverse radical species. To test whether KP772 can protect cells from reactive oxygen species (ROS), KB-3-1 cells were treated in presence of subtoxic concentrations of KP772 (0.5 and 1 μM) with various concentrations of H 2 O 2 .…”

Section: Resultsmentioning

confidence: 99%

Ribonucleotide Reductase as One Important Target of [Tris(1,10- phenanthroline)lanthanum(III)] Trithiocyanate (KP772)

Heffeter

Popović‐Bijelić²,

Saiko³

et al. 2009

CCDT

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KP772 is a new lanthanum complex containing three 1,10-phenathroline molecules. Recently, we have demonstrated that the promising in vitro and in vivo anticancer properties of KP772 are based on p53-independent G(0)G(1) arrest and apoptosis induction. A National Cancer Institute (NCI) screen revealed significant correlation of KP772 activity with that of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU). Consequently, this study aimed to investigate whether KP772 targets DNA synthesis in tumor cells by RR inhibition. Indeed, KP772 treatment led to significant reduction of cytidine incorporation paralleled by a decrease of deoxynucleoside triphosphate (dNTP) pools. This strongly indicates disruption of RR activity. Moreover, KP772 protected against oxidative stress, suggesting that this drug might interfere with RR by interaction with the tyrosyl radical in subunit R2. Additionally, several observations (e.g. increase of transferrin receptor expression and protective effect of iron preloading) indicate that KP772 interferes with cellular iron homeostasis. Accordingly, co-incubation of Fe(II) with KP772 led to generation of a coloured iron complex (Fe-KP772) in cell free systems. In electron paramagnetic resonance (EPR) measurements of mouse R2 subunits, KP772 disrupted the tyrosyl radical while Fe-KP772 had no significant effects. Moreover, coincubation of KP772 with iron-loaded R2 led to formation of Fe-KP772 suggesting chelation of RR-bound Fe(II). Summarizing, our data prove that KP772 inhibits RR by targeting the iron centre of the R2 subunit. As also Fe-KP772 as well as free lanthanum exert significant -though less pronounced- cytotoxic/static activities, additional mechanisms are likely to synergise with RR inhibition in the promising anticancer activity of KP772.

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“…It is variously reported that ribonucleotide reductase inhibitors may have anticarcinogenic effects and induce apoptosis (15) or may be endowed with the possibility to inhibit the induction of apoptosis via oxidative stress (54). This enzyme seems to be only marginally involved in the apoptosis of CGCs since its inhibition by hydroxyurea (55) has only a small effect both in improving cell survival and reducing superoxide anion levels.…”

Section: Discussionmentioning

confidence: 99%

Different sources of reactive oxygen species contribute to low potassium-induced apoptosis in cerebellar granule cells

Bobba

Atlante²,

Petragallo³

et al. 2008

Int J Mol Med

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Abstract. An early increase in ROS production is characteristic of cerebellar granule cells undergoing apoptosis in the presence of 5 mM KCl. However, the sources of this increase have not been investigated in detail. In particular whether there is a single enzymatic source or the increase in ROS production is the consequence of the involvement of different enzymes has not been studied in depth. Different enzymatic pathways may indeed contribute to the upregulation of intracellular ROS production either directly or via side-chain reactions and a number of candidate enzymes are known to be involved in the apoptotic process in various cell types. The aim of this study was to identify the cellular sources of the ROS generated by CGCs undergoing apoptosis by low K + . A panel of specific inhibitors against phospholipase, cytochromes P450, cyclooxygenase, lipoxygenase, xanthine oxidase, ribonucleotide reductase and NADPH oxidase were used. We provide evidence that no single source of ROS can be identified in apoptotic CGCs, but the ROS generated through the arachidonic acid (AA) pathways, mainly via lipoxygenase activities, seems to be the most prominent.

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Preventive Effect of Trimidox on Oxidative Stress in U937 Cell Line

Cited by 7 publications

References 23 publications

Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity

Ribonucleotide Reductase as One Important Target of [Tris(1,10- phenanthroline)lanthanum(III)] Trithiocyanate (KP772)

Different sources of reactive oxygen species contribute to low potassium-induced apoptosis in cerebellar granule cells

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