Inhibition of tumoral cell respiration and growth by nordihydroguaiaretic acid

Pavani, Mario; Fones, Elizabeth; Oksenberg, Danny; Garcia, Manuel Barrios; Hernández, Carolina; Cordano, G.; Muñoz, Sergio; Mancilla, Jerson; Guerrero, Antonio José Moreno; Ferreira, Jorge

doi:10.1016/0006-2952(94)90592-4

Cited by 32 publications

(25 citation statements)

References 39 publications

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“…It is, however, unlikely that this effect of the drug is due to its well known inhibitory effect on lipoxygenase pathways of arachidonic acid metabolism, since other selective inhibitors against the pathways including caffeic acid, circumin, and esculetin did not affect protein secretion even at considerably high concentrations (0.1-0.2 mM) (data not shown). NDGA also caused the reduction of cellular ATP levels, as was previously shown by experiments in vitro (39,40) and in vivo (41). Although intracellular protein transport is critically dependent on the cellular ATP level (42,43), we assume that the reduction of the cellular ATP level by NDGA observed here is not directly related to the inhibition of protein transport.…”

Section: Discussionsupporting

confidence: 51%

Nordihydroguaiaretic Acid Blocks Protein Transport in the Secretory Pathway Causing Redistribution of Golgi Proteins into the Endoplasmic Reticulum

Fujiwara¹,

Takami²,

Misumi³

et al. 1998

Journal of Biological Chemistry

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We have investigated the effect of nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, on the intracellular protein transport and the structure of the Golgi complex. Pulse-chase experiments and immunoelectron microscopy showed that NDGA strongly inhibits the transport of newly synthesized secretory proteins to the Golgi complex resulting in their accumulation in the endoplasmic reticulum (ER). Despite their retention in the ER, oligosaccharides of secretory and ER-resident proteins were processed to endoglycosidase H-resistant forms, raising the possibility that oligosaccharide-processing enzymes are redistributed from the Golgi to the ER. Morphological observations further revealed that ␣-mannosidase II (a cis/medial-Golgi marker), but not TGN38 (a trans-Golgi network marker), rapidly redistributes to the ER in the presence of NDGA, resulting in the disappearance of the characteristic Golgi structure. Upon removal of the drug, the Golgi complex was reassembled into the normal structure as judged by perinuclear staining of ␣-mannosidase II and by restoration of the secretion. These effects of NDGA are quite similar to those of brefeldin A. However, unlike brefeldin A, NDGA did not cause a dissociation of ␤-coatomer protein, a subunit of coatomer, from the Golgi membrane. On the contrary, NDGA exerted the stabilizing effect on ␤-coatomer protein/membrane interaction against the dissociation caused by brefeldin A and ATP depletion. Taken together, these results indicate that NDGA is a potent agent disrupting the structure and function of the Golgi complex with a mechanism different from those known for other drugs reported so far.

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Section: Discussionsupporting

confidence: 51%

Nordihydroguaiaretic Acid Blocks Protein Transport in the Secretory Pathway Causing Redistribution of Golgi Proteins into the Endoplasmic Reticulum

Fujiwara¹,

Takami²,

Misumi³

et al. 1998

Journal of Biological Chemistry

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“…Several reports in the literature (14,15) and in this laboratory 2 also suggest that lipoxygenase metabolites including 15-LO metabolites can act as inhibitors of apoptosis. However, NDGA is a general inhibitor of lipoxygenases and can influence the redox state of cells (48,49), so this conclusion must be viewed with caution. We considered directly testing the 15-LO metabolites of arachidonic acid and linoleic acid, but the high binding of the metabolites to proteins and other materials in the tissue culture system severely compromises this approach.…”

Section: Discussionmentioning

confidence: 99%

Expression of 15-Lipoxygenase by Human Colorectal Carcinoma Caco-2 Cells during Apoptosis and Cell Differentiation

Kamitani

Geller

Eling

1998

Journal of Biological Chemistry

130

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We studied arachidonic acid metabolism and the expression of cyclooxygenase (Cox) and 15-lipoxygenase (15-LO) in the human colorectal carcinoma cell line, Caco-2, which undergo apoptosis and cell differentiation in the presence of sodium butyrate (NaBT). Caco-2 cells expressed very low levels of Cox-1 but highly expressed Cox-2. NaBT treatment shifted the arachidonic acid metabolites by cell lysates from prostaglandins to 15-hydroxyeicosatetraenoic acid, indicating the presence of a 15-LO. Linoleic acid, an excellent substrate for 15-LO, was metabolized poorly by the Caco-2 cells, but NaBT treatment shifted metabolism to 15-LO metabolite, 13(S)-hydroxyoctadecadienoic acid. Caco-2 cells expressed a 15-LO but only after treatment with NaBT, as determined by Northern blotting. Immunoblotting with anti-human 15-LO antibody detected a 72-kDa band in NaBT-treated Caco-2 cells. Expression of 15-LO mRNA was dependent on the duration of NaBT treatment, with the highest expression observed between 10 and 24 h. Results from expression and metabolism studies with arachidonic and linoleic acid cells indicated Cox-2 was responsible for the lipid metabolism in control cells, whereas 15-LO was the major enzyme responsible after NaBT induction of apoptosis and cell differentiation. The 15-LO in Caco-2 cells was characterized as human reticulocyte 15-LO by reverse transcription-polymerase chain reaction and restriction enzyme analysis. The expression of 15-LO and 15-hydroxyeicosatetraenoic acid or 13(S)-hydroxyoctadecadienoic acid formation correlates with cell differentiation or apoptosis in Caco-2 cells induced by NaBT. The addition of nordihydroguaiaretic acid, a lipoxygenase inhibitor, significantly increased NaBT-induced apoptosis, whereas the addition of indomethacin did not alter NaBT-induced apoptosis in the Caco-2 cells. However, indomethacin treatment decreased the expression of Cox-2 in NaBT-treated cells and significantly increased the expression of 15-LO during NaBT treatment. These studies suggest a role for 15-LO, in addition to Cox-2, in modulating NaBT-induced apoptosis and cell differentiation in human colorectal carcinoma cells.The first genetic alteration in the multistep process that leads to the development of colon carcinogenesis seems to be the loss of APC gene function. Investigations of APC function and its mutations have provided important clues in understanding colon cancer (1). One of the important changes that results from the loss of the APC gene function is the overexpression of prostaglandin H synthase-2 (cyclooxygenase-2, Cox-2), 1 an inducible enzyme that converts arachidonic acid to prostaglandins. The link between APC, Cox-2, and polyp formation was firmly established in studies using APC (Apc ⌬716 ) and Cox-2 knockout mice (2). Mice carrying the APC mutation overexpress Cox-2 and develop intestinal polyps. When bred to mice with the disrupted Cox-2 gene, the offspring, homozygously deficient for Cox-2, had significantly less polyps than the mice with wild-type Cox-2. These results confirmed C...

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“…In addition to its antioxidative effects, it inhibits lipoxygenase isoenzymes (LOX) (Ding et al 1999;Yamamoto et al 1987), transport channels (Wang et al 1993) and cellular respiration (Pavani et al 1994). Moreover, it was also shown to prevent both activation of carcinogens and tumor promotion in mouse skin (Belman et al 1989;Wang et al 1991) and in the bladder (Yu et al 1992).…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring lignans efficiently induce apoptosis in colorectal tumor cells

Hausott

Greger

Marian

2003

Journal of Cancer Research and Clinical Oncology

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Plant-derived lignans caused cell loss by apoptosis in colorectal adenoma and carcinoma cells. Nordihydroguaiaretic acid (NDGA), commonly used for the inhibition of lipoxygenase isoenzymes, showed the strongest growth inhibition with an IC50 of 1.9+/-0.5 microg followed by epiashantin (IC50=9.8+/-4.5 microM) and arctigenin (IC50=16.5+/-8.5 microM). The lignans caused a time- and dose-dependent loss of mitochondrial membrane potential (MMP), down regulation of the anti-apoptotic protein bcl(xl) and an increase of the apoptotic index. The time interval until loss of MMP and down modulation of bcl(xl) became evident correlated with the efficiency of growth inhibition by NDGA, epiashantin and yangambin. Bcl2 and caspase 3 were not involved. NDGA also induced a shift of the culture population to the G2/M phase of the cell cycle. With respect to these results, naturally occurring lignans could be useful in the therapy and chemoprevention of colorectal tumors.

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Inhibition of tumoral cell respiration and growth by nordihydroguaiaretic acid

Cited by 32 publications

References 39 publications

Nordihydroguaiaretic Acid Blocks Protein Transport in the Secretory Pathway Causing Redistribution of Golgi Proteins into the Endoplasmic Reticulum

Nordihydroguaiaretic Acid Blocks Protein Transport in the Secretory Pathway Causing Redistribution of Golgi Proteins into the Endoplasmic Reticulum

Expression of 15-Lipoxygenase by Human Colorectal Carcinoma Caco-2 Cells during Apoptosis and Cell Differentiation

Naturally occurring lignans efficiently induce apoptosis in colorectal tumor cells

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