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Science Forum Index » Life Extension Forum » ROS-generating mitochondrial DNA mutations can...
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 Posted: Tue May 13, 2008 11:32 am |
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The ROS scavengers used in the study to inhibit metastasis were NAC
and ebselen (a glutathione peroxidase mimetic). NAC has been used in
preclinical studies to inhibit metastasis.
"...reversible regulation of metastasis....with ROS scavengers
suggests that metastasis of these cells is regulated by ROS-mediated
reversible upregulationof nuclear genes but not by ROS-mediated
acceleration of genetic instability."
Science. 2008 May 2;320(5876):661-4. Epub 2008 Apr 3. Links
ROS-generating mitochondrial DNA mutations can regulate tumor cell
metastasis.Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi
A, Imanishi H, Nakada K, Honma Y, Hayashi J.
Graduate School of Life and Environmental Sciences, University of
Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
Mutations in mitochondrial DNA (mtDNA) occur at high frequency in
human tumors, but whether these mutations alter tumor cell behavior
has been unclear. We used cytoplasmic hybrid (cybrid) technology to
replace the endogenous mtDNA in a mouse tumor cell line that was
poorly metastatic with mtDNA from a cell line that was highly
metastatic, and vice versa. Using assays of metastasis in mice, we
found that the recipient tumor cells acquired the metastatic potential
of the transferred mtDNA. The mtDNA conferring high metastatic
potential contained G13997A and 13885insC mutations in the gene
encoding NADH (reduced form of nicotinamide adenine dinucleotide)
dehydrogenase subunit 6 (ND6). These mutations produced a deficiency
in respiratory complex I activity and were associated with
overproduction of reactive oxygen species (ROS). Pretreatment of the
highly metastatic tumor cells with ROS scavengers suppressed their
metastatic potential in mice. These results indicate that mtDNA
mutations can contribute to tumor progression by enhancing the
metastatic potential of tumor cells.
PMID: 18388260 [PubMed - in process] |
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| Posted: Tue May 13, 2008 11:34 am |
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J Nutr Biochem. 2006 Dec;17(12):837-46. Epub 2006 Mar 24. Links
Phenylethyl isothiocyanate and its N-acetylcysteine conjugate suppress
the metastasis of SK-Hep1 human hepatoma cells.Hwang ES, Lee HJ.
Department of Food Science and Technology, School of Agricultural
Biotechnology and Center for Agricultural Biomaterials, College of
Agriculture and Life Sciences, Seoul National University, San 56-1,
Shillim-dong, Gwanak-gu 151-921, Republic of Korea.
Phenylethyl isothiocyanate (PEITC), a hydrolysis compound of
gluconasturtiin, is metabolized to N-acetylcysteine (NAC)-PEITC in the
body after the consumption of cruciferous vegetables. We observed an
inhibitory effect of PEITC and its metabolite NAC-PEITC on cancer cell
proliferation, adhesion, invasion, migration and metastasis in SK-Hep1
human hepatoma cells. PEITC and NAC-PEITC suppressed SK-Hep1 cell
proliferation in a dose-dependent manner, and exposure to 10 microM
PEITC or NAC-PEITC reduced cell proliferation by 25% and 30%,
respectively. NAC-PEITC inhibited cancer cell adhesion, invasion and
migration to a similar or to an even larger degree than PEITC. The
expression of matrix metalloproteinase (MMP) 2, MMP-9 and membrane
type 1 matrix metalloproteinase (MT1-MMP) is a known risk factor for
metastatic disease. Gelatin zymography analysis revealed a significant
downregulation of MMP-2/MMP-9 protein expression in SK-Hep1 cells
treated with 0.1-5 microM PEITC or NAC-PEITC. PEITC and NAC-PEITC
treatment caused dose-dependent decreases in MMP-2/MMP-9 and MT1-MMP
mRNA levels, as determined by reverse transcription polymerase chain
reaction. PEITC and NAC-PEITC also increased the mRNA levels of tissue
inhibitors of matrix metalloproteinase (TIMPs) 1 and 2. Our data
suggest that this inhibition is mediated by downregulation of MMP and
upregulation of TIMPs.
PMID: 16563723 [PubMed - indexed for MEDLINE] |
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| Posted: Tue May 13, 2008 11:36 am |
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Am J Pathol. 2004 May;164(5):1683-96. Links
N-acetyl-cysteine promotes angiostatin production and vascular
collapse in an orthotopic model of breast cancer.Agarwal A, Muñoz-
Nájar U, Klueh U, Shih SC, Claffey KP.
Department of Physiology, University of Connecticut Health Center,
Farmington, Connecticut 06030-3501, USA.
The antioxidant N-acetyl-cysteine (NAC) has been shown to be
chemopreventive in clinical studies, and in recent studies, has shown
promise in preventing tumor progression. Although the effects of NAC
on tumorigenesis have been associated with decreased angiogenesis, the
mechanism of the anti-angiogenic activity has not been determined. In
the following study, we describe a novel mechanism whereby NAC therapy
blocks MDA-MB-435 breast carcinoma cell proliferation and metastasis
in an in vivo tumorigenic model. Athymic nude mice bearing MDA-MB-435
xenografts were treated with systemic NAC daily for 8 weeks. NAC
treatment resulted in endothelial cell apoptosis and reduction of
microvascular density within the core of the tumor leading to
significant tumor cell apoptosis/necrosis. Angiostatin accumulated in
tumors from NAC-treated but not control animals. Additional studies
using a vascular endothelial growth factor-dependent chicken
chorioallantoic membrane angiogenic assay recapitulated NAC-induced
endothelial apoptosis and coordinate production of angiostatin, a
potent endothelial apoptotic factor. In vitro studies showed
angiostatin was formed in endothelial cultures in a vascular
endothelial growth factor- and NAC-dependent manner, a process that
requires endothelial cell surface plasminogen activation. These
results suggest that systemic NAC therapy promotes anti-angiogenesis
through angiostatin production, resulting in endothelial apoptosis and
vascular collapse in the tumor.
PMID: 15111315 [PubMed - indexed for MEDLINE]
PMCID: PMC1615662 |
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| Posted: Tue May 13, 2008 11:37 am |
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| Posted: Tue May 13, 2008 11:38 am |
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Cancer Sci. 2004 Jan;95(1):18-24. Links
Suppression of metastasis by nuclear factor kappaB inhibitors in an in
vivo lung metastasis model of chemically induced hepatocellular
carcinoma.Futakuchi M, Ogawa K, Tamano S, Takahashi S, Shirai T.
Department of Experimental Pathology and Tumor Biology, Graduate
School of Medical Sciences, Nagoya City University, Mizuho-ku, Nagoya
467-8601, Japan. futakuch at (no spam) med.nagoya-cu.ac.jp
To evaluate the suppressive effects of nuclear factor kappa B (NF-
kappaB) inhibitors on metastasis, three agents, pentoxifylline (PTX,
0.5% in diet), N-acetyl-L-cysteine (NAC, 0.5% in diet), and aspirin
(ASP, 0.5% in diet) were applied in an in vivo highly metastatic rat
hepatocellular carcinoma (HCC) model in F344 male rats. Administration
of NF-kappaB inhibitors for 8 weeks after induction of highly
metastatic HCC by sequential treatment with diethylnitrosamine and N-
nitrosomorpholine did not cause any significant change in survival
rate or body weight. The incidence of HCC was 100% at week 23,
regardless of treatment with NF-kappaB inhibitors. PTX, NAC, and ASP
did not exert any significant effect on the development or
differentiation of HCCs, although PTX tended to decrease the
multiplicity of HCC. Although no lung metastasis was observed in the
rats killed at the end of the period of carcinogen exposure, lung
metastasis was found in 100% of animals in all the groups at the end
of the experiment. Multiplicity of lung metastasis was significantly
decreased by PTX and NAC, whereas ASP was without significant
influence. The size of metastatic nodules was also significantly
reduced in the PTX treatment group. Furthermore, the inhibitory kappa-
B (IkappaB) protein level, considered to be a marker for the degree of
NF-kappaB transcription, was significantly suppressed by PTX. mRNA
expression in HCC for vascular cell adhesion molecule-1 (VCAM-1),
which is considered to play a key role in attachment of cancer cells
to the endothelium, was significantly suppressed by PTX. Among the
splicing variants of VEGF, VEGF-A120, VEGF-A144, VEGF-A164, and VEGF-
A188, suppressed mRNA expression of VEGF-A188 appeared to be
correlated with suppression of lung metastasis formation. In
conclusion, the present study demonstrated that NF-kappaB inhibitors
have the potential to inhibit lung metastasis from rat HCCs in vivo,
and PTX is especially promising. Its mechanism of action may involve
suppression of VCAM-1 and VEGF-A188 production.
PMID: 14720322 [PubMed - indexed for MEDLINE] |
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| Taka... |
| Posted: Tue May 13, 2008 2:54 pm |
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On May 14, 6:32 am, timoth... at (no spam) my-deja.com wrote:
Quote: The ROS scavengers used in the study to inhibit metastasis were NAC
and ebselen (a glutathione peroxidase mimetic). NAC has been used in
preclinical studies to inhibit metastasis.
"...reversible regulation of metastasis....with ROS scavengers
suggests that metastasis of these cells is regulated by ROS-mediated
reversible upregulationof nuclear genes but not by ROS-mediated
acceleration of genetic instability."
Science. 2008 May 2;320(5876):661-4. Epub 2008 Apr 3. Links
ROS-generating mitochondrial DNA mutations can regulate tumor cell
metastasis.Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yamaguchi
A, Imanishi H, Nakada K, Honma Y, Hayashi J.
Graduate School of Life and Environmental Sciences, University of
Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8572, Japan.
Mutations in mitochondrial DNA (mtDNA) occur at high frequency in
human tumors, but whether these mutations alter tumor cell behavior
has been unclear. We used cytoplasmic hybrid (cybrid) technology to
replace the endogenous mtDNA in a mouse tumor cell line that was
poorly metastatic with mtDNA from a cell line that was highly
metastatic, and vice versa. Using assays of metastasis in mice, we
found that the recipient tumor cells acquired the metastatic potential
of the transferred mtDNA. The mtDNA conferring high metastatic
potential contained G13997A and 13885insC mutations in the gene
encoding NADH (reduced form of nicotinamide adenine dinucleotide)
dehydrogenase subunit 6 (ND6). These mutations produced a deficiency
in respiratory complex I activity and were associated with
overproduction of reactive oxygen species (ROS). Pretreatment of the
highly metastatic tumor cells with ROS scavengers suppressed their
metastatic potential in mice. These results indicate that mtDNA
mutations can contribute to tumor progression by enhancing the
metastatic potential of tumor cells.
PMID: 18388260 [PubMed - in process]
If you got so far to have a metastatic cancer you can feed the ROS-
overproducing cells some Omega-3 fats and let them kill themselves ...
Taka |
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