Apoptosis and inhibition of gap-junctional intercellular communication induced by LA-12, a novel hydrophobic platinum(IV) complex

Procházka, Lubomír; Tuřánek, Jaroslav; Tesařı́k, Radek; Knotigová, Pavlína Turánek; Polaskova, Pavlina; Andrysík, Zdeněk; Kozubı́k, Alois; F, Zak; Sova, Petr; Neužil, Jiřı́; Machala, Miroslav

doi:10.1016/j.abb.2007.03.021

Cited by 23 publications

(24 citation statements)

References 29 publications

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“…It was reported that platinum-based reagents, including cisplatin, affected GJIC by reducing the amount or inducing aberrant intracellular localization of connexin proteins, or by regulating the mitogen-activated protein kinase-dependent phosphorylation of specific sites on connexins (Fiorini et al, 2004;Zhao et al, 2004;Prochá zka et al, 2007). However, the effects reported here on purified, reconstituted connexin channels establish that inhibition can occur by direct interaction of cisplatin/oxaliplatin with connexin protein and that this has a detrimental effect on toxic efficacy.…”

Section: Downloaded Fromcontrasting

confidence: 48%

Cisplatin and Oxaliplatin Inhibit Gap Junctional Communication by Direct Action and by Reduction of Connexin Expression, Thereby Counteracting Cytotoxic Efficacy

Wang

You²,

Yuan³

et al. 2010

J Pharmacol Exp Ther

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Cisplatin [cis-diamminedichloroplatinum(II)]/oxaliplatin [1,2-diamminocyclohexane(trans-1)oxolatoplatinum(II)] toxicity is enhanced by functional gap junctions between treated cells, implying that inhibition of gap junctions may decrease cytotoxic activity of these platinum-based agents. This study investigates the effect of gap junction modulation by cisplatin/oxaliplatin on cytotoxicity in a transformed cell line. The effects were explored using junctional channels expressed in transfected HeLa cells and purified hemichannels. Junctional channels showed a rapid, dose-dependent decrease in dye coupling with exposure to cisplatin/oxaliplatin. With longer exposure, both compounds also decreased connexin expression. Both compounds inhibit the activity of purified connexin hemichannels, over the same concentration range that they inhibit junctional dye permeability, demonstrating that inhibition occurs by direct interaction of the drugs with connexin protein. Cisplatin/oxaliplatin reduced the clonogenic survival of HeLa cells at low density and high density in a dose-dependent manner, but to a greater degree at high density, consistent with a positive effect of gap junctional intercellular communication (GJIC) on cytotoxicity. Reduction of GJIC by genetic or pharmacological means decreased cisplatin/oxaliplatin toxicity. At low cisplatin/oxaliplatin concentrations, where effects on connexin channels are minimal, the toxicity increased with increased cell density. However, higher concentrations strongly inhibited GJIC, and this counteracted the enhancing effect of greater cell density on toxicity. The present results indicate that inhibition of GJIC by cisplatin/ oxaliplatin decreases their cytotoxicity. Direct inhibition of GJIC and reduction of connexin expression by cisplatin/oxaliplatin may thereby compromise the effectiveness of these compounds and be a factor in the development of resistance to this class of chemotherapeutic agents.

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Section: Downloaded Fromcontrasting

confidence: 48%

Cisplatin and Oxaliplatin Inhibit Gap Junctional Communication by Direct Action and by Reduction of Connexin Expression, Thereby Counteracting Cytotoxic Efficacy

Wang

You²,

Yuan³

et al. 2010

J Pharmacol Exp Ther

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“…They also found the inhibitory effect of GJIC was induced by hyperphosphorylation of Cx43 protein which decrease the localization of cell membrane, which correlated with activation of MAP kinase pathway proteins. On the other hand CDDP exerted only a low effect on GJIC though the drug caused activation of MAP kinase protein (Procházka et al, 2007). Another report which supports Procházka et al showed that Cx43 level was elevated in CDDP-resistant cell line (Li et al, 2007).…”

Section: Gap Junction Dependent Mannersupporting

confidence: 68%

“…Because it is known that CDDP toxicity is modulated by a MAP kinase pathway besides the established mechanisms (Park et al, 2002;Woessmann et al, 2002) and that Cxs are regulated by multiple mechanisms, including MAP kinase dependent phosphorylation (Jo et al, 2005;Lampe & Lau, 2004;Wang et al, 2000). Procházka et al showed a new platinum complex, LA-12, had strong GJIC inhibiting effect (Procházka et al, 2007). They also found the inhibitory effect of GJIC was induced by hyperphosphorylation of Cx43 protein which decrease the localization of cell membrane, which correlated with activation of MAP kinase pathway proteins.…”

Section: Gap Junction Dependent Mannermentioning

confidence: 99%

“…One of the previous reports suggests a posibility that CDDP could affect GJIC, it might be regulated by MAP kinase-dependent phosphorylation of specific sites of Cx43 (Procházka et al, 2007). Because it is known that CDDP toxicity is modulated by a MAP kinase pathway besides the established mechanisms (Park et al, 2002;Woessmann et al, 2002) and that Cxs are regulated by multiple mechanisms, including MAP kinase dependent phosphorylation (Jo et al, 2005;Lampe & Lau, 2004;Wang et al, 2000).…”

Section: Gap Junction Dependent Mannermentioning

confidence: 99%

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Connexin 43 Enhances the Cisplatin-Induced Cytotoxicity in Mesothelioma Cells

Behnam-Mothlag¹,

Tyler²,

Brännström³

et al. 2012

Mesotheliomas - Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnos

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“…Almost every cellular and tissuelevel process is affected by this communication pathway, including differentiation, migration, and apoptosis (7,8). Many studies have shown that gap junctions play important roles in cancer biology and drug resistance (9,10).…”

mentioning

confidence: 99%

Tramadol and Flurbiprofen Depress the Cytotoxicity of Cisplatin via Their Effects on Gap Junctions

Tong

Wang

et al. 2009

Clinical Cancer Research

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Purpose: Cancer patients are often concurrently treated with analgesics and antineoplastic drugs, yet the influence of analgesic agents on therapeutic activity of antineoplastic drugs is largely unexplored. This study investigates the effects of three commonly used analgesics, which produce analgesia by different mechanisms, on cytotoxicity induced by cisplatin, a widely used antitumor agent, and the relation between those effects and modulation of gap junction function by the analgesics. Experimental Design: The role of gap junctions in the modulation of cisplatin toxicity is explored by manipulation of connexin expression, and gap junction presence and function, using clinically relevant concentrations of the analgesics and cisplatin. Results: Short-term exposure of transformed cells to cisplatin reduced the clonogenic survival in low-density cultures (without gap junction formation) and in high density (with gap junction formation), but the toxic effect was greater at high density. In the absence of connexin expression or with block of connexin channels, cell density had no effect on cisplatin toxicity. Tramadol and flurbiprofen, but not morphine, significantly reduced cisplatin cytotoxicity, but this effect required functional gap junctions between the cells. Tramadol and flurbiprofen inhibited dye-coupling through gap junctions, but morphine did not. Conclusions:The results suggest that the density dependence of cisplatin toxicity is mediated by gap junctions. They further indicate that tramadol and flurbiprofen depress cisplatin cytotoxicity through inhibition of gap junction activity, and more generally, that agents that depress junctional communication can counteract the effects of antitumor agents. (Clin Cancer Res 2009;15(18):5803-10)

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Apoptosis and inhibition of gap-junctional intercellular communication induced by LA-12, a novel hydrophobic platinum(IV) complex

Cited by 23 publications

References 29 publications

Cisplatin and Oxaliplatin Inhibit Gap Junctional Communication by Direct Action and by Reduction of Connexin Expression, Thereby Counteracting Cytotoxic Efficacy

Cisplatin and Oxaliplatin Inhibit Gap Junctional Communication by Direct Action and by Reduction of Connexin Expression, Thereby Counteracting Cytotoxic Efficacy

Connexin 43 Enhances the Cisplatin-Induced Cytotoxicity in Mesothelioma Cells

Tramadol and Flurbiprofen Depress the Cytotoxicity of Cisplatin via Their Effects on Gap Junctions

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