Mitochondria Permeabilization by a Novel Polycation Peptide BTM-P1

Lemeshko, Victor V.; Arias, Mauricio; Ordúz, Sergio

doi:10.1074/jbc.m414064200

Cited by 19 publications

(19 citation statements)

References 64 publications

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“…Another factor that could possibly contribute to the higher activity of these toxins in the isolated midgut assay is the presence of an inside-negative electrical potential across the membrane, at least at the beginning of the experiment, which is absent during the vesicle assay. Such a potential was previously found, on the basis of theoretical (Biggin and Sansom, 1996) and experimental (Lemeshko et al, 2005) data, to enhance the insertion of a-helical peptides corresponding to segments of the putative pore-forming domain of different Cry toxins. However, in the case of the whole toxin, a detailed study of this possibility would probably necessitate a more elaborate experimental setup than that used in the present study in which membrane potential measurements are used to evaluate pore formation.…”

Section: Discussionmentioning

confidence: 88%

Midgut juice components affect pore formation by the Bacillus thuringiensis insecticidal toxin Cry9Ca

Brunet¹,

Vachon²,

Marsolais³

et al. 2010

Journal of Invertebrate Pathology

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Section: Discussionmentioning

confidence: 88%

Midgut juice components affect pore formation by the Bacillus thuringiensis insecticidal toxin Cry9Ca

Brunet¹,

Vachon²,

Marsolais³

et al. 2010

Journal of Invertebrate Pathology

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“…( Lemeshko et al, 2005) Butylated hydroxylanisole Chemoprevention Induces PT in isolated mitochondria. (Yu et al, 2000) Butyrate Chemoprevention Induces PT in isolated mitochondria and ANT proteoliposomes.…”

Section: Btm-p1mentioning

confidence: 99%

Mitochondria as therapeutic targets for cancer chemotherapy

et al. 2006

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Mitochondria are vital for cellular bioenergetics and play a central role in determining the point-of-no-return of the apoptotic process. As a consequence, mitochondria exert a dual function in carcinogenesis. Cancer-associated changes in cellular metabolism (the Warburg effect) influence mitochondrial function, and the invalidation of apoptosis is linked to an inhibition of mitochondrial outer membrane permeabilization (MOMP). On theoretical grounds, it is tempting to develop specific therapeutic interventions that target the mitochondrial Achilles' heel, rendering cancer cells metabolically unviable or subverting endogenous MOMP inhibitors. A variety of experimental therapeutic agents can directly target mitochondria, causing apoptosis induction. This applies to a heterogeneous collection of chemically unrelated compounds including positively charged a-helical peptides, agents designed to mimic the Bcl-2 homology domain 3 of Bcl-2-like proteins, ampholytic cations, metals and steroid-like compounds. Such MOMP inducers or facilitators can induce apoptosis by themselves (monotherapy) or facilitate apoptosis induction in combination therapies, bypassing chemoresistance against DNA-damaging agents. In addition, it is possible to design molecules that neutralize inhibitor of apoptosis proteins (IAPs) or heat shock protein 70 (HSP70). Such IAP or HSP70 inhibitors can mimic the action of mitochondrion-derived mediators (Smac/DIABLO, that is, second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point, in the case of IAPs; AIF, that is apoptosis-inducing factor, in the case of HSP70) and exert potent chemosensitizing effects.

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“…Measurement of the Inner Membrane Potential-The inner membrane potential of mitochondria was monitored fluorometrically using safranin O as described previously (17). Mitochondria, 0.5 mg of protein/ml, were added to SKPH medium supplemented with 5 mM succinate-KOH and 10 M safranin O.…”

Section: Methodsmentioning

confidence: 99%

Synergistic Inhibition of Mitochondrial Respiration by Anticancer Agent Erucylphosphohomocholine and Cyclosporin A

Lemeshko

Kugler

2007

Journal of Biological Chemistry

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Alkylphosphocholines are a new class of anticancer agents. The mechanisms by which these drugs display their antitumor activities are not known. In this work, we show that erucylphosphohomocholine, a new antineoplastic compound, significantly decreased ATP synthesis in isolated rat liver mitochondria at a concentration of 50 M or higher via permeabilization of the inner membrane. At a concentration of 25 M, it induced a moderate swelling of mitochondria, a slight decrease of the inner membrane potential, and an increase in state 4 respiration without an essential influence on state 3 respiration or the outer membrane permeability to cytochrome c. We found that cyclosporin A did not prevent mitochondrial swelling induced by 25-100 M erucylphosphohomocholine. Moreover, cyclosporin A induced a fast drop of the inner membrane potential in the presence of 25-50 M erucylphosphohomocholine that seems to be due to a strong synergistic inhibition of the respiratory activity. The ratio of uncoupled to state 3 respiration rates increased from 1.3 ؎ 0.1 with 25 M erucylphosphohomocholine and from 1.5 ؎ 0.1 with 1 M cyclosporin A to 4.5 ؎ 0.3 in the presence of both drugs. On the other hand, oligomycin or cyclosporin A protected certain cancer cell lines against erucylphosphohomocholine-induced apoptosis. This protection might be related to a prevention of cellular ATP hydrolysis by permeabilized mitochondria and to the inhibition of the classical permeability transition pore, respectively. Our findings provide new insight into the mechanisms by which these unusual alterations of mitochondria might be involved in anticancer activity of alkylphosphocholines.Alkylphosphocholines are a new class of antitumor agents, which target biomembranes and induce cancer cell apoptosis (1-3). Erucylphosphohomocholine (ErPC3), 2 one of the most effective alkylphosphocholines, has been shown to be a promising preclinical anticancer agent (4 -7). The precise mechanisms of antineoplastic activity of alkylphosphocholines are unknown. It has been found that they are working through p53-independent pathways (2, 8) involving mitochondrial alteration, cytochrome c release, and caspase-3 activation (9). Our previous studies have shown that the pro-apoptotic activity of ErPC3 is associated with an increased production of reactive oxygen species (10) and might be blocked by ligands of the peripheral-type benzodiazepine receptor (11), which is located in the outer membrane of mitochondria in close proximity to the voltage-dependent anion channel (12).In this work, we have found that in addition to pro-apoptotic activities, ErPC3 is also able to decrease ATP synthesis in isolated rat liver mitochondria. Our data showed that the ErPC3-mediated decrease of ATP synthesis involves a direct cyclosporin A (CsA)-insensitive permeabilization of the inner membrane. We have also discovered an unusual synergistic inhibition of ADP-dependent respiration of mitochondria in the presence of both CsA and ErPC3. The mechanism of this effect does not seem to be directly ...

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Mitochondria Permeabilization by a Novel Polycation Peptide BTM-P1

Cited by 19 publications

References 64 publications

Midgut juice components affect pore formation by the Bacillus thuringiensis insecticidal toxin Cry9Ca

Midgut juice components affect pore formation by the Bacillus thuringiensis insecticidal toxin Cry9Ca

Mitochondria as therapeutic targets for cancer chemotherapy

Synergistic Inhibition of Mitochondrial Respiration by Anticancer Agent Erucylphosphohomocholine and Cyclosporin A

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