Paradoxical Cellular Effects and Biological Role of the Multifaceted Compound Nordihydroguaiaretic Acid

• Published in: Archiv der Pharmazie (Weinheim) 2014-10, Vol.347 (10), p.685-697
• Main Authors: Hernández-Damián, Jacqueline, Andérica-Romero, Ana Cristina, Pedraza-Chaverri, José
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antioxidant; Antioxidant Response Elements - drug effects; Antioxidants; Antitumoral activity; Drug Design; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; Gene Expression Regulation; Humans; Lipoxygenase Inhibitors - chemistry; Lipoxygenase Inhibitors - pharmacology; Masoprocol - chemistry; Masoprocol - pharmacology; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Structure; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; NF-E2-Related Factor 2 - metabolism; Nordihydroguaiaretic acid; Nrf2; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.201400159

Nordihydroguaiaretic acid (NDGA) is a phenolic compound obtained from the leaves of the evergreen desert shrub Larrea tridentata (Creosote bush), which has been used anciently in folk medicine for the treatment of multiple diseases. At the molecular level, NDGA is a potent scavenger of reactive oxygen species. Lipoxygenase inhibition by NDGA has been broadly studied over several cell models; however, NDGA exerts other antioxidant properties and cytoprotective effects in non‐tumor cells, which are related with its role as modulator of the nuclear factor erythroid 2‐related factor 2 (Nrf2)/antioxidant response element (ARE) antioxidant pathway. In contrast, in tumor cells NDGA exerts pro‐apoptotic activity and anti‐tumor effects. Different effects of NDGA have been observed in mitochondria, where NDGA prevents mitochondrial damage in non‐tumor cells and induces loss of mitochondrial function in tumor cells. Moreover, NDGA exerts beneficial effects in diverse diseases like cancer, renal damage, Huntington's disease, Alzheimer's disease, and other neurodegenerative pathologies. This work represents a critical review about relevant NDGA mechanisms, cellular effects, and signal pathways involved with possible useful effects. Nordihydroguaiaretic acid (NDGA) modulates several signaling pathways and promotes different cellular processes. Intriguingly, in normal cells, NDGA protects against cell damage while in tumor cells it promotes apoptosis and cell death. These features of NDGA reside in its ROS scavenging capacity and its diverse cellular targets.