Protonophoric Activity of Ellipticine and Isomers across the Energy-transducing Membrane of Mitochondria

Schwaller, M. A.; Allard, Bruno; Lescot, Elie; Moreau, F

doi:10.1074/jbc.270.39.22709

Cited by 48 publications

(33 citation statements)

References 24 publications

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“…Therefore, acute ellipticine toxicity to UKF-NB-3 cells might be caused by its intercalation into DNA and/or inhibition of topoisomerase II, or by uncoupling mitochondrial oxidative phosphorylation and disrupting the cell's energy balance [10]. At the present time, we can only speculate on the mechanism explaining the different responses of UKF-NB-3 to ellipticine.…”

mentioning

confidence: 72%

“…Ellipticine also uncouples mitochondrial oxidative phosphorylation [10] and thereby disrupts the energy A c c e p t e d M a n u s c r i p t 5 balance of cells. Ellipticine and 9-hydroxyellipticine also cause selective inhibition of p53 protein phosphorylation in several human cancer cell lines [11,12], and this correlates with their cytotoxic activity.…”

Section: ) An Alkaloid Isolated Frommentioning

confidence: 99%

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The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

Poljaková

Eckschlager

Hraběta

et al. 2009

Biochemical Pharmacology

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Ellipticine is an antineoplastic agent, whose mode of action is based mainly on DNA intercalation, inhibition of topoisomerase II and formation of covalent DNA adducts mediated by cytochromes P450 and peroxidases. Here, the molecular mechanism of DNA-mediated ellipticine action in human neuroblastoma IMR-32, UKF-NB-3 and UKF-NB-4 cancer cell lines was investigated. Treatment of neuroblastoma cells with ellipticine resulted in apoptosis induction, which was verified by the appearance of DNA fragmentation, and in inhibition of cell growth. These effects were associated with formation of two covalent ellipticine-derived DNA adducts, identical to those formed by the cytochrome P450-and peroxidase-mediated ellipticine metabolites, 13-hydroxy-and 12-hydroxyellipticine. The expression of these enzymes at mRNA and protein levels and their ability to generate ellipticine-DNA adducts in neuroblastoma cells were proven, using the real-time polymerase chain reaction, Western blotting analyses and by analyzing ellipticine-DNA adducts in incubations of this drug with neuroblastoma S9 fractions, enzyme cofactors and DNA. The levels of DNA adducts correlated with toxicity of ellipticine to IMR-32 and UKF-NB-4 cells, but not with that to UKF-NB-3 cells. In addition, hypoxic cell culture conditions resulted in a decrease in ellipticine toxicity to IMR-32 and UKF-NB-4 cells and this correlated with lower levels of DNA adducts. Both these cell lines accumulated in S phase, suggesting that ellipticine-DNA adducts interfere with DNA replication. The results demonstrate that among the multiple modes of ellipticine antitumor action, formation of covalent DNA adducts by ellipticine is the predominant mechanism of cytotoxicity to IMR-32 and UKF-NB-4 neuroblastoma cells.

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mentioning

confidence: 72%

Section: ) An Alkaloid Isolated Frommentioning

confidence: 99%

The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

Poljaková

Eckschlager

Hraběta

et al. 2009

Biochemical Pharmacology

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“…The scheme is similar to that for conventional anionic protonophore except for the sign of the charged form moving across the membrane. A similar mechanism was proposed for the protonophorous action of the cationic antitumor alkaloid ellipticine (11) and pyridine AU-1421 (13). Our scheme differs from that for ellipticine by the intramembrane location of the carrier due to high affinity of SkQR1 and C 12 R1 with membranes (20).…”

Section: Discussionmentioning

confidence: 99%

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Antonenko

Avetisyan

Cherepanov

et al. 2011

Journal of Biological Chemistry

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A limited decrease in mitochondrial membrane potential can be beneficial for cells, especially under some pathological conditions, suggesting that mild uncouplers (protonophores) causing such an effect are promising candidates for therapeutic uses. The great majority of protonophores are weak acids capable of permeating across membranes in their neutral and anionic forms. In the present study, protonophorous activity of a series of derivatives of cationic rhodamine 19, including dodecylrhodamine (C 12 R1) and its conjugate with plastoquinone (SkQR1), was revealed using a variety of assays. Derivatives of rhodamine B, lacking dissociable protons, showed no protonophorous properties. In planar bilayer lipid membranes, separating two compartments differing in pH, diffusion potential of H ؉ ions was generated in the presence of C 12 R1 and SkQR1. These compounds induced pH equilibration in liposomes loaded with the pH probe pyranine. C 12 R1 and SkQR1 partially stimulated respiration of rat liver mitochondria in State 4 and decreased their membrane potential. Also, C 12 R1 partially stimulated respiration of yeast cells but, unlike the anionic protonophore FCCP, did not suppress their growth. Loss of function of mitochondrial DNA in yeast (grande-petite transformation) is known to cause a major decrease in the mitochondrial membrane potential. We found that petite yeast cells are relatively more sensitive to the anionic uncouplers than to C 12 R1 compared with grande cells. Together, our data suggest that rhodamine 19-based cationic protonophores are self-limiting; their uncoupling activity is maximal at high membrane potential, but the activity decreases membrane potentials, which causes partial efflux of the uncouplers from mitochondria and, hence, prevents further membrane potential decrease.Transport of electrons along the mitochondrial respiratory chain is accompanied by the formation of an electrochemical gradient of hydrogen ions (⌬ H ϩ) 3 at the inner mitochondrial membrane. ⌬ H ϩ is used for ATP production and other energyconsuming processes. However, high values of ⌬ H ϩ can increase the production of dangerous reactive oxygen species (ROS) (1, 2). Although mitochondria are able to control ⌬ H ϩ by adjusting the activity of natural uncoupling mechanisms (i.e. free fatty acids, anion carriers, and uncoupling proteins) (3), there is considerable interest in finding pharmacological agents to increase mitochondrial proton leak and, as a consequence, to prevent obesity and to decrease ROS production (4 -7).Uncouplers, or protonophores, are small organic compounds capable of carrying hydrogen ions across artificial and biological membranes. The strategy of "mild uncoupling" (2) relies on the fact that partial decrease in ⌬ H ϩ can be beneficial for cells especially under some pathological conditions, suggesting that uncouplers are good candidates for therapeutic uses. Apparently, such applications are hindered by high toxicity, as in the case of 2,4-dinitrophenol (DNP), which was temporarily used at the beg...

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“…Ellipticine causes an increase in the protein expression of p53 and, p21/WAF1 and KIP1/p27, but not of WAF1/p21 in human breast adenocarcinoma MCF-7 cells treated with ellipticine, and growth inhibition by this compound is also induced by mitochondrial proapoptotic pathways in these cells 19 . In addition, ellipticines uncouple mitochondrial oxidative phosphorylation 20 , and thereby disrupt the energy balance of cells.…”

Section: Mechanisms Of the Cytotoxicity And Anticancer Activity Of Elmentioning

confidence: 99%

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

Stiborová¹,

Rupertová²,

Schmeiser³

et al. 2006

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Ellipticine is a potent antineoplastic agent exhibiting the multimodal mechanism of its action. This article reviews the mechanisms of predominant pharmacological and cytotoxic effects of ellipticine and shows the results of our laboratories indicating a novel mechanism of its action. The prevalent mechanisms of ellipticine antitumor, mutagenic and cytotoxic activities were suggested to be intercalation into DNA and inhibition of DNA topoisomerase II activity. We demonstrated a new mode of ellipticine action, formation of covalent DNA adducts mediated by its oxidation with cytochromes P450 (CYP) and peroxidases. The article reports the molecular mechanism of ellipticine oxidation by CYPs and identifies human and rat CYPs responsible for ellipticine metabolic activation and detoxication. It also presents a role of peroxidases (i.e. myeloperoxidase, cyclooxygenases, lactoperoxidase) in ellipticine oxidation leading to ellipticine-DNA adducts. The 9-hydroxy-and 7-hydroxyellipticine metabolites formed by CYPs and the major product of ellipticine oxidation by peroxidases, the dimer, in which the two ellipticine skeletons are connected via N 6 of the pyrrole ring of one ellipticine molecule and C9 in the second one, are the detoxication metabolites. On the contrary, 13-hydroxy-and 12-hydroxyellipticine, produced by ellipticine oxidation with CYPs, the latter one formed also spontaneously from another CYP-and peroxidase-mediated metabolite, ellipticine N 2 -oxide, are metabolites responsible for formation of two ellipticine-derived deoxyguanosine adducts in DNA. The results reviewed here allow us to propose species, two carbenium ions, ellipticine-13-ylium and ellipticine-12-ylium, as reactive species generating two major DNA adducts seen in vivo in rats treated with ellipticine. The study forms the basis to further predict the susceptibility of human cancers to ellipticine.

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Protonophoric Activity of Ellipticine and Isomers across the Energy-transducing Membrane of Mitochondria

Cited by 48 publications

References 24 publications

The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

The mechanism of cytotoxicity and DNA adduct formation by the anticancer drug ellipticine in human neuroblastoma cells

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Molecular Mechanisms of Antineoplastic Action of an Anticancer Drug Ellipticine

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