Nordihydroguaiaretic acid (NDGA)

NDGA has been proven to selectively inhibit arachidonic acid 5-lipoxygenase activity, which reduces leukotriene and prostaglandin synthesis, thus leading to a reduction of inflammatory pathways. NDGA also has profound effects on the secretory pathway, reflected in its ability to block production of leukotriene B4, degranulation, phagocytosis, and the respiratory burst by exerting effects on the mitochondria and nonspecifically inhibiting NADPH oxidase and protein kinase C. NDGA has also been shown to block protein transport from the endoplasmic reticulum (ER) to the Golgi complex, induce the redistribution of Golgi proteins into the ER and affect levels of intracellular calcium. Furthermore, NDGA has been shown to disrupt the actincytoskeleton and exert effects on cell adhesion and also to directly inhibit activationof two receptor tyrosine kinases (RTKs), the Insulin-like growth factor-1 receptor and the c-erbB2/HER2/neu receptor, that results in decreased cellular proliferation. NDGA selectively inhibits platelet-derived growth factor (PDGF)-stimulated DNA synthesis in Swiss 3T3 cells, diploid murine cells and rat and human fibroblasts. NDGA is a bioactive natural product which is able to crosslink collagen. NDGA cross-linking may provide a viable approach to stabilizing collagenous materials for use in repair of ruptured, lacerated or surgically transected tendons, as well as other biomaterial constructs for surgical repair of musculoskeletal injuries and disease^[1].

Adding 0.1% NDGA to the drinking water of athymic mice bearing non-small cell lung cancer tumors significantly inhibits tumor growth compared with control mice. In addition, NDGA has not only been shown to suppress breast cancer cell growth, it has a synergistic effect with retinoic acid on the inhibition of mammary tumor cell transformation and proliferation. Preliminary in vivo studies have revealed that NDGA suppresses tumor growth by inhibiting metabolic enzymes as well as RTK phosphorylation, which is overexpressed in certain cancer cells. NDGA has also been proven to be a potent anti-ischemia-reperfusion injury agent in vitro and in animal models through different antioxidant pathways. It has been identified as a compound capable of inducing glutamate uptake and upregulation of expression levels and activity of the glutamate transporter EAAT2 (GLT-1) in mice^[1].

• Cell lines

  PC3 cells

• Concentrations

  10-50 μM

• Incubation Time

  16 h

• Method

  Cytotoxicity tests are carried out using WST-1, a fluorescent cell proliferation reagent. The assay is based on cleavage of the tetrazolium salt WST-1 by active mitochondria to produce a soluble colored formazan salt. The cells are plated at 1 × l0⁴ in 96-well microtiter plates. Twenty-four hours after plating, at 70% confluence the growth medium is removed and replaced with the test solutions (100 ìl). After 16-hr exposure, the reaction medium (in the presence or absence of 10-50 μM NDGA) is removed, the cells are washed twice with culture medium, then 100 μl culture medium and 10 μl WST-1 are added to each well. The cells are incubated for 2 hrs at 37 °C in a humidified atmosphere with 5% CO2, then the microplate is thoroughly shaken for 1 min and the absorbance is measured at 450 nm using a microtiter reader.

• Animal Models

  Male Swiss albino mice

• Dosages

  1 and 2 mg/animal/day

• Administration

  oral