Inhibition of Mitochondrial NADH Oxidase, Succinoxidase, and ATPase by Naturally Occurring Flavonoids

Bohmont, Craig W.; Aaronson, Laura M.; Mann, Kathy; Pardini, Ronald S.

doi:10.1021/np50051a014

Cited by 37 publications

(28 citation statements)

References 17 publications

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“…Chrysin, for instance, was a very potent inducer of intracellular GSH depletion in A549 cells, but showed relatively low toxicity after 48 h of treatment. Apigenin and genistein, which were reported to be inhibitors of complex I of the mitochondrial respiratory chain, were relatively toxic in the three cell types, whereas kaempferol was not an inhibitor of complex I and was less toxic (Table 4) [5]. However, the contribution of MRP-mediated GSH depletion to the toxicity of flavonoids and other prooxidants cannot be discarded.…”

Section: Potentiation Of Tumor Cell Cytotoxicitymentioning

confidence: 99%

“…5A). Chrysin was also reported to inhibit complex I of the mitochondrial respiratory chain [5]; yet, at 25 µM, it induced little change in O 2…”

Section: Potentiation Of Tumor Cell Cytotoxicitymentioning

confidence: 99%

“…Besides their anti-and prooxidant properties in vitro, they appear to exert modulatory effects in cells through alterations of protein and lipid kinase signaling pathways [2,3]. A number of flavonoids behave as prooxidants by inhibiting complexes I and II of the mitochondrial respiratory chain [4][5][6]. Moreover, several flavonoids induce glutathione (GSH) depletion through activation of multidrug resistance protein 1 (MRP1), an ATP-binding cassette (ABC) transporter [7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Flavonoid-induced glutathione depletion: Potential implications for cancer treatment

Kachadourian

Day

2006

Free Radical Biology and Medicine

123

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The ability of a number of flavonoids to induce glutathione (GSH) depletion was measured in lung (A549), myeloid (HL-60), and prostate (PC-3) human tumor cells. The hydroxychalcone (2′-HC) and the dihydroxychalcones (2′,2-, 2′,3-, 2′,4-, and 2′,5′-DHC) were the most effective in A549 and HL-60 cells, depleting more than 50% of intracellular GSH within 4 h of exposure at 25 µM. In contrast, the flavones chrysin and apigenin were the most effective in PC-3 cells, depleting 50-70% of intracellular GSH within 24 h of exposure at 25 µM. In general, these flavonoids were more effective than three classical substrates of multidrug resistance protein 1 (MK-571, indomethacin, and verapamil). Prototypic flavonoids (2′,5′-DHC and chrysin) were subsequently tested for their abilities to potentiate the toxicities of prooxidants (etoposide, rotenone, 2-methoxyestradiol, and curcumin). In A549 cells, 2′,5′-DHC potentiated the cytotoxicities of rotenone, 2-methoxyestradiol, and curcumin, but not etoposide. In HL-60 and PC-3 cells, chrysin potentiated the cytotoxicity of curcumin, cytotoxicity that was attenuated by the catalytic antioxidant manganese(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP). Assessments of mitochondrial GSH levels mitochondrial membrane potential and cytochrome c release showed that the potentiation effects induced by 2′,5′-DHC and chrysin involve mitochondrial dysfunction.

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Section: Potentiation Of Tumor Cell Cytotoxicitymentioning

confidence: 99%

“…5A). Chrysin was also reported to inhibit complex I of the mitochondrial respiratory chain [5]; yet, at 25 µM, it induced little change in O 2…”

Section: Potentiation Of Tumor Cell Cytotoxicitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Flavonoid-induced glutathione depletion: Potential implications for cancer treatment

Kachadourian

Day

2006

Free Radical Biology and Medicine

123

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“…It has been also demonstrated that, under the phenoxyl radical form, polyphenols can cause mitochondrial toxicity by collapsing the mitochondrial transmembrane potential, thereby allowing ROS being generated at high extent [19]. Moreover it has been reported that several natural-occurring flavonoids, and trans-resveratrol itself, are able to affect mitochondrial respiration [24] by inhibiting NADH oxidase, succinoxidase and ATP synthesis [3], thus inducing the generation of partially reduced oxygen species [26,48]. Particularly, a direct relationship between flavonoids redox potential and the above mentioned mitochondrial phenomena, has been proposed [25].…”

Section: Introductionmentioning

confidence: 99%

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

et al. 2007

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Polyphenols represent a large class of plantderived molecules with a general chemical structure that act as potent free radical scavengers. They have long been recognized to possess several therapeutic activities ranging from anti-thrombotic to antioxidant. Moreover, the capability of polyphenols to act as reducing or oxidizing molecules depends on the presence of environmental metals and on the concentrations used. In this work we demonstrated that the stilbene trans-resveratrol was able to commit human breast cancer MCF-7 cells to apoptosis. Mainly, we evidenced a pivotal role of the mitochondria in this phenomenon as cytochrome c release into the cytosol was found after the treatment. We further showed that trans-resveratrol was able to affect cellular redox state. In particular, it induced an early production of ROS and lipid oxidation, and only later compromised the GSH/GSSG ratio. This mode of action was mirrored by a temporally different activation of JNK and p38 MAPK , with the former rapidly induced and the latter weakly activated at long intervals. The results obtained demonstrate a pro-apoptotic activity for trans-resveratrol, and suggest a preferential activation of different classes of MAP kinases in response to different oxidative stimuli (ROS versus GSH/GSSG alteration).

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“…In the case of flavonoids, however, their chemopreventive properties may rather rely on eliminating precancerous cells due to their pro-oxidant properties in vivo. This is likely the case of apigenin and ChR, in which their cytotoxicity may result from a combination of interference with the mitochondrial respiratory chain and MRP-mediated GSH depletion (34)(35)(36). Intracellular ROS mediates multiple cellular responses, including protein kinase activation (37), cell cycle progression (38), myeloid cell differentiation (39,40) and apoptosis (41).…”

Section: Discussionmentioning

confidence: 99%

Induction of apoptosis by 5,7-dihydroxy-8-nitrochrysin in breast cancer cells: The role of reactive oxygen species and Akt

Zhao

Tian²,

Cao³

et al. 2010

Int J Oncol

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Abstract. 5,7-dihydroxy-8-nitrochrysin (NOC), a novel synthetic chrysin analogue, induces apoptosis in human cancer cells. We previously demonstrated that NOC possesses stronger cytotoxicity towards human colon carcinoma and human gastric carcinoma cells than chrysin. Herein, we demonstrate the mechanism by which NOC preferentially suppresses the viability of the MDA-MB-453 human breast cancer cell line (ER negative, Her2 overexpressing) and moderately suppresses the viability of the MCF-7 cell line (ER positive, Her2 low), but has little effect on the immortalized non-cancerous HBL-100 breast cell line (ER positive, Her2 low). Moreover, the results of our studies, for the first time, provide mechanistic evidence that NOC induces apoptosis by the generation of reactive oxygen species and Akt dephosphorylation. Our findings highlight a new mechanism responsible for NOC-induced apoptosis, and raise the possibility that NOC might be promising as a candidate for human breast cancer therapy.

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Inhibition of Mitochondrial NADH Oxidase, Succinoxidase, and ATPase by Naturally Occurring Flavonoids

Cited by 37 publications

References 17 publications

Flavonoid-induced glutathione depletion: Potential implications for cancer treatment

Flavonoid-induced glutathione depletion: Potential implications for cancer treatment

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

Induction of apoptosis by 5,7-dihydroxy-8-nitrochrysin in breast cancer cells: The role of reactive oxygen species and Akt

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