Avicins, natural anticancer saponins, permeabilize mitochondrial membranes

Lemeshko, Victor V.; Haridas, Valsala; Perez, J.C.; Gutterman, Jordan U.

doi:10.1016/j.abb.2006.08.008

Cited by 53 publications

(43 citation statements)

References 59 publications

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“…Mitochondrial Swelling-Mitochondrial swelling was monitored simultaneously with the inner membrane potential using a modified cuvette holder for the Aminco-Bowman-2 luminescence spectrometer to allow the measurement of 90°dispersion of light emitted by the red light-emitting diode attached as described earlier (18). All mitochondrial samples were constantly stirred with a magnetic stirrer and maintained at constant temperature of 30°C.…”

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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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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“…However, the direct influence of avicins on mitochondria was corroborated by two recent reports. The first underlined the ability of avicins to induce the outer mitochondrial membrane permeabilisation which leads to decrease respiratory activity (Lemeshko et al 2006). The second demonstrated that avicins reduce the rate of respiration and levels of ATP in Jurkat cells after inhibition of the voltage dependent anion channel in the outer mitochondrial membrane (Haridas et al 2007).…”

Section: Acaciosidesmentioning

confidence: 98%

A review of acacic acid-type saponins from Leguminosae-Mimosoideae as potent cytotoxic and apoptosis inducing agents

et al. 2011

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“…No data exists yet on the salinity tolerance of species closely related to A. victoriae. A. victoriae is of interests also due to its seed pods being a source of Avicins, which have a strong potential as anti-tumor drugs (Lemeshko, Haridas, Quijano-Pérez, & Gutterman, 2006).…”

Section: Discussionmentioning

confidence: 99%

Rapid Identification of Acacia Species With Potential Salt Tolerance by Using Nuclear Ribosomal DNA Markers

Joseph¹,

Bhave²,

Miller³

et al. 2013

SAR

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Use of saline lands for agroforestry relies primarily on plant species that have the trait of salinity tolerance, and also other economic and agronomic benefits. The selection of species, however, also needs to consider other key factors such as compatibility with existing flora, and potential for environmental benefits such as improved soil fertility or lowering of the water table in the case of dryland salinity. The testing of candidate species in particular environments needs substantial investments of costs and time. In this paper, a novel approach is presented for the rapid identification of potentially salt tolerant Acacia species, based on molecular phylogenetic analysis. The approach has been applied to four species groups, Acacia pendula, A. salicina, A. victoriae and A. stenophylla. The nuclear-encoded ribosomal DNA internal and external transcribed spacer (ITS and ETS) regions were used as markers, and phylogenetic analyses undertaken to identify closely related species that may share the salt tolerance traits. Such a methodology could be used to more rapidly identify candidate native species for agroforestry in salinity-affected regions and for preventing further expansion of salinity, thus assisting in biodiversity conservation.

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Avicins, natural anticancer saponins, permeabilize mitochondrial membranes

Cited by 53 publications

References 59 publications

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

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

A review of acacic acid-type saponins from Leguminosae-Mimosoideae as potent cytotoxic and apoptosis inducing agents

Rapid Identification of Acacia Species With Potential Salt Tolerance by Using Nuclear Ribosomal DNA Markers

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