PMID: 

Br J Cancer. 2002 Apr 8 ;86(7):1188-96. PMID: 11953870

Abstract Title: 

Mechanisms of nordihydroguaiaretic acid-induced growth inhibition and apoptosis in human cancer cells.

Abstract: 

Lipoxygenase metabolites of arachidonic acid can act as growth promoting factors for various cancer cell lines. Here we demonstrate that the 5-lipoxygenase inhibitor nordihydroguaiaretic acid potently inhibits anchorage-independent growth of human pancreatic and cervical cancer cells in soft agar and delays growth of pancreatic and cervical tumours established in athymic mice. Furthermore, nordihydroguaiaretic acid induces apoptosis of these cancer cells in vitro and in vivo. Potential mechanisms mediating these effects of nordihydroguaiaretic acid were examined. Nordihydroguaiaretic acid had no inhibitory effect on growth and survival signals such as tyrosine phosphorylation of the epidermal growth factor receptor or basal and growth factor-stimulated activities of extracellular signal-regulated kinase 1/2, p70(s6k) and AKT but selectively inhibited expression of cyclin D1 in the cancer cells. In addition, treatment with nordihydroguaiaretic acid lead to a disruption of the filamentous actin cytoskeleton in human pancreatic and cervical cancer cells which was accompanied by the activation of Jun-NH(2)-terminal kinase and p38(mapk). Similar effects were obtained by treatment of the cancer cells with cytochalasin D. These results suggest that nordihydroguaiaretic acid induces anoikis-like apoptosis as a result of disruption of the actin cytoskeleton in association with the activation of stress activated protein kinases. In conclusion, nordihydroguaiaretic acid could constitute a lead compound in the development of novel therapeutic agents for various types of cancer.

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PMID: 

Cancer Detect Prev. 2005 ;29(3):276-85. Epub 2005 Feb 17. PMID: 15936596

Abstract Title: 

Sensitization of colon cancer cell lines to butyrate-mediated proliferation inhibition by combined application of indomethacin and nordihydroguaiaretic acid.

Abstract: 

The aim of the study was to investigate the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on histone deacetylase-mediated proliferation inhibition. In the colon cancer cell line HT29 butyrate-mediated proliferation inhibition was enhanced by the additional presence of indomethacin (IM) and/or nordihydroguaiaretic acid (NDGA). Sensitisation to butyrate-mediated proliferation inhibition was abolished by the general caspase inhibitor Z-VAD-fmk, however, only IM-induced cell detachment was prevented by the caspase inhibitor but not that induced by NDGA or NDGA plus IM. In contrast to the parental cell line HT29, in the methotrexate-resistant sub-lines HT29-12 and HT29-21, IM counteracted butyrate-mediated proliferation inhibition, which was abrogated by NDGA. In all the investigated cell lines, proliferation inhibition was most effectively achieved under the combined application of butyrate with IM and NDGA, suggesting that inhibition of both cyclooxygenase (COX) and lipoxygenase (LOX) isoenzymes is needed for proliferation inhibition by NSAIDs in tumour cells.

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PMID: 

Mutat Res. 1991 Nov ;261(3):153-62. PMID: 1719406

Abstract Title: 

Antimutagenic and antitumorigenic activities of nordihydroguaiaretic acid.

Abstract: 

Nordihydroguaiaretic acid (NDGA), which occurs in the resinous exudates of many plants is used as an antioxidant in fats and oils. In this study we show that NDGA inhibited the mutagenicity of methyl methanesulfonate, benzo[a]pyrene (BP), 2-aminofluorene, and aflatoxin B1 in Salmonella typhimurium strain TA100 or TA98 in the absence and presence of rat hepatic microsomal activation system. The addition of NDGA during and after nitrosation of methylurea (MU) resulted in a dose-dependent inhibition of mutagenicity induced by nitrosation products of MU. In a two-stage skin tumorigenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor promoter, pretreatment of animals with NDGA prior to DMBA application, afforded significant protection against skin tumorigenicity in female SENCAR mice. In additional studies, skin application of NDGA also inhibited the binding of topically applied [3H]BP and [3H]DMBA to epidermal DNA. When assessed in the anti-tumor promotion protocol, pretreatment of animals with NDGA before each application of TPA in DMBA-initiated mouse skin, resulted in 72% decrease in the total number of tumors when compared to non-NDGA pretreated animals. The possible mechanism(s) of the antimutagenic and anti-tumorigenic activities may be due to the multiple effects of NDGA as inhibitor of the carcinogen metabolism and DNA-adduct formation, scavenger of carcinogen free radicals, and as inhibitor of TPA-induced ornithine decarboxylase activity.

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PMID: 

Intervirology. 2005 ;48(5):336-40. PMID: 15956802

Abstract Title: 

Inhibition of influenza-virus-induced apoptosis in chorion cells of human fetal membranes by nordihydroguaiaretic Acid.

Abstract: 

OBJECTIVES: It has been postulated that the pathogenesis of influenza virus infection involves not only the virus-proliferation-mediated apoptotic cell death in infected cells, but also a direct reactive oxygen species (ROS)-induced cellular injury in the infected organs. We examined effects of an antioxidant, nordihydroguaiaretic acid (NDGA), on apoptosis induction and viral proliferation. Subsequently, the results were compared with those of pyrrolidine dithiocarbamate (PDTC), another antioxidant.METHODS: The levels of ROS production were measured with 2',7'-dichlorofluorescein diacetate; apoptosis induction and viral proliferation were analyzed by DNA fragmentation and plaque-forming assays, respectively.RESULTS: The treatment of infected cells with NDGA inhibited ROS overproduction, apoptotic DNA fragmentation and virus proliferation. The maximum inhibition against DNA fragmentation (76%) was observed with 500 microM NDGA. The antiviral activity of NDGA against influenza virus was more potent than that of PDTC.CONCLUSIONS: The present study, therefore, suggests for the first time that NDGA, a known antioxidant reagent, inhibits the induction of apoptosis in human fetal membrane chorion cells infected with influenza virus through the more potent antiviral activity than that of PDTC.

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PMID: 

Clin Cancer Res. 2005 Jun 15 ;11(12):4601-9. PMID: 15958646

Abstract Title: 

Systemic treatment with tetra-O-methyl nordihydroguaiaretic acid suppresses the growth of human xenograft tumors.

Abstract: 

PURPOSE: We have previously shown that the transcriptional inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) induces growth arrest in tumor cells and exhibits tumoricidal activity when injected intratumorally into tumor cell explants in mice. The experiments reported here were designed to determine whether M(4)N can be given systemically and inhibit the growth of five different human xenograft tumors.EXPERIMENTAL DESIGN: Nude (nu/nu) mice bearing xenografts of each of five human tumor types (i.e., hepatocellular carcinoma, Hep 3B; prostate carcinoma, LNCaP; colorectal carcinoma, HT-29; breast carcinoma, MCF7; and erythroleukemia, K-562) were treated with M4N given i.v. or i.p. in a Cremophor EL-based solvent system or orally in a corn oil based diet. Tumors from the treated animals were measured weekly and analyzed for the expression of the Cdc2 and survivin genes, both previously shown to be down-regulated by M4N.RESULTS: Systemic M4N treatment suppressed the in vivo growth of xenografts in each of the five human tumor types. Four of the five tumor models were particularly sensitive to M4N with tumor growth inhibitions (T/C values) of

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PMID: 

Zhonghua Bing Li Xue Za Zhi. 2000 Feb ;29(1):30-3. PMID: 11866889

Abstract Title: 

[The effect of nordihydroguaiaretic acid on endothelial cell migration induced by glioma cells].

Abstract: 

OBJECTIVE: To investigate the effect of nordihydroguaiaretic acid (NDGA) on the migration of endothelial cells (ECs) induced by glioma cells (GCs) in vitro.METHODS: Cells of human umbilical vein endothelial cell line ECV-304 and human malignant glioma cell line SHG-44 were co-cultured in the Falcon Cell Culture Insert system, and the effect of NDGA on the migration of ECs induced by GCs was investigated. The expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) was examined with immunohistochemistry.RESULTS: The expressions of VEGF and bFGF in SHG-44 cells were reduced after treatment with 100 micromol/L NDGA for 1 to 3 days. 100 micromol/L NDGA significantly inhibited not only the chemotactic migration of ECs induced by either glioma cells or glioma-conditioned media, but also the random motility of ECs (P

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PMID: 

Leuk Lymphoma. 2007 Apr ;48(4):774-85. PMID: 17454637

Abstract Title: 

Tetra-O-methyl nordihydroguaiaretic acid inhibits growth and induces death of leukemia cells independent of Cdc2 and survivin.

Abstract: 

Tetra-O-methyl nordihydroguaiaretic acid (M4N) was shown to induce G2 arrest and suppress human xenograft tumor growth by inhibiting Cdc2 and survivin. We examined the effect of M4N on leukemia and found that M4N inhibited growth and induced cell death in leukemic cell lines and blasts from AML patients. However, no significant changes in Cdc2 and survivin levels and G2 arrest were observed. Cell death and growth inhibition were dependent neither on XIAP, Bcl-2, and Bcl-X(L) levels nor on caspase-8. M4N did not promote cell differentiation in HL-60 cells. Interestingly, significant inhibition of AKT phosphorylation was observed in M4N treated OCI-AML3 cells. Collectively, our data showed that M4N inhibited cell growth and induced cell death in both leukemic cell lines and AML patient sample via a mechanism not mediated by Cdc2 and survivin inhibition and suggested that the extrinsic and the mitochondrial apoptotic pathways are not essential.

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PMID: 

Hepatology. 2011 Dec ;54(6):1936-46. PMID: 21858850

Abstract Title: 

Effects of hypolipidemic agent nordihydroguaiaretic acid on lipid droplets and hepatitis C virus.

Abstract: 

UNLABELLED: Hepatitis C virus (HCV) relies on host lipid metabolic pathways for its replication, assembly, secretion, and entry. HCV induces de novo lipogenesis, inhibitsβ-oxidation, and lipoprotein export resulting in a lipid-enriched cellular environment critical for its proliferation. We investigated the effects of a hypolipidemic agent, nordihydroguaiaretic acid (NDGA), on host lipid/fatty acid synthesis and HCV life cycle. NDGA negated the HCV-induced alteration of host lipid homeostasis. NDGA decreased sterol regulatory element binding protein (SREBP) activation and enhanced expression of genes involved in β-oxidation. NDGA inhibited very low-density lipoprotein (VLDL) secretion by affecting mediators of VLDL biosynthesis. Lipid droplets (LDs), the neutral lipid storage organelles, play a key role in HCV morphogenesis. HCV induces accumulation and perinuclear distribution of LDs, whereas NDGA most notably reduced the overall number and increased the average size of LDs. The antiviral effects of NDGA resulted in reduced HCV replication and secretion.CONCLUSION: NDGA-mediated alterations of host lipid metabolism, LD morphology, and VLDL transport appear to negatively influence HCV proliferation.

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PMID: 

Cancer Res. 2001 Jul 15 ;61(14):5499-504. PMID: 11454698

Abstract Title: 

Tetra-O-methyl nordihydroguaiaretic acid induces G2 arrest in mammalian cells and exhibits tumoricidal activity in vivo.

Abstract: 

The transcription inhibitor tetra-O-methyl nordihydroguaiaretic acid (M4N) was found to arrest the proliferation of C3, C33a, CEM-T4, and TC-1 cells in culture at the G2 stage of the cell cycle. Investigation into the mechanism of arrest revealed that M4N reduces mRNA levels and subsequent protein production of the cyclin-dependent kinase CDC2, resulting in the inactivation of the CDC2/cyclin B complex (maturation promoting factor). When injected intratumorally in a C3-cell induced C57bl/6 mouse tumor model system, M4N demonstrated substantial tumoricidal activity that correlated with a reduction in tumor cell CDC2 protein levels. These findings suggest that M4N may be a useful chemotherapeutic agent for the control of unregulated cellular proliferation.

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PMID: 

Brain Res. 1994 Aug 15 ;654(1):171-6. PMID: 7982093

Abstract Title: 

Nordihydroguaiaretic acid protects hippocampal neurons against amyloid beta-peptide toxicity, and attenuates free radical and calcium accumulation.

Abstract: 

Recent findings indicate that amyloid beta-peptide (A beta) can be neurotoxic by a mechanism involving an increase in the concentration of intracellular free Ca2+ ([Ca2+]i) and the generation of free radicals. In the present study, the lipoxygenase inhibitor/antioxidant nordihydroguaiaretic acid (NDGA) protected cultured rat hippocampal neurons against the toxicity of A beta in a concentration-dependent manner. Measurements of cellular oxidation (using the oxidation-sensitive dye 2,7-dichlorofluorescin) and intracellular free Ca2+ levels (using the Ca2+ indicator dye fura-2), showed that NDGA suppressed A beta-induced accumulation of reactive oxygen species (ROS) and Ca2+; Ca2+ responses to glutamate were also suppressed by NDGA. NDGA prevented neuronal injury and accumulation of ROS induced by iron, indicating a role for NDGA as an antioxidant in NDGA-mediated neuroprotection. Another lipoxygenase inhibitor (AA861) also protected against A beta and iron toxicity whereas the the 5-lipoxygenase-activating protein inhibitor L655,238 and the cyclooxygenase inhibitor indomethacin were ineffective. These findings suggest that NDGA can interupt a neurodegenerative pathway relevant to the pathophysiology of Alzheimer's disease.

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