Tetra-O-Methyl Nordihydroguaiaretic Acid Broadly Suppresses Cancer Metabolism and Synergistically Induces Strong Anticancer Activity in Combination with Etoposide, Rapamycin and UCN-01

Abstract

The ability of Tetra-O-methyl nordihydroguaiaretic acid (M4N) to induce rapid cell death in combination with Etoposide, Rapamycin, or UCN-01 was examined in LNCaP cells, both in cell culture and animal experiments. Mice treated with M4N drug combinations with either Etoposide or Rapamycin showed no evidence of tumor and had a 100% survival rate 100 days after tumor implantation. By comparison all other vehicles or single drug treated mice failed to survive longer than 30 days after implantation. This synergistic improvement of anticancer effect was also confirmed in more than 20 cancer cell lines. In LNCaP cells, M4N was found to reduce cellular ATP content, and suppress NDUFS1 expression while inducing hyperpolarization of mitochondrial membrane potential. M4N-treated cells lacked autophagy with reduced expression of BNIP3 and ATG5. To understand the mechanisms of this anticancer activity of M4N, the effect of this drug on three cancer cell lines (LNCaP, AsPC-1, and L428 cells) was further examined via transcriptome and metabolomics analyses. Metabolomic results showed that there were reductions of 26 metabolites essential for energy generation and/or production of cellular components in common with these three cell lines following 8 hours of M4N treatment. Deep RNA sequencing analysis demonstrated that there were sixteen genes whose expressions were found to be modulated following 6 hours of M4N treatment similarly in these three cell lines. Six out of these 16 genes were functionally related to the 26 metabolites described above. One of these up-regulated genes encodes for CHAC1, a key enzyme affecting the stress pathways through its degradation of glutathione. In fact M4N was found to suppress glutathione content and induce reactive oxygen species production. The data overall indicate that M4N has profound specific negative impacts on a wide range of cancer metabolisms supporting the use of M4N combination for cancer treatments.

Glyoxalase 2 drives tumorigenesis in human prostate cells in a mechanism involving androgen receptor and p53‐p21 axis

“…LNCaP cells transfected with control siRNA (siCtr) or Glo2 siRNA (siGlo2) for 24 h were exposed to the anticancer drugs docetaxel (D, 20 μM) and rapamycin (R, 20 μM) or to the apoptotic inducer staurosporine (STS, 1 μM) for additional 48 h. Biological effects were, therefore, evaluated 72 h post‐siCtr or siGlo2 transfection. DHT is a potent agonist activating androgen receptor.…”

Antiviral Activity of Nordihydroguaiaretic Acid and Its Derivative Tetra- O -Methyl Nordihydroguaiaretic Acid against West Nile Virus and Zika Virus

“…However, our CC 50 values for each compound evidenced that M 4 N displayed a reduced toxicity in comparison to that of NDGA. In fact, despite the high similarity in the molecular structures of NDGA and M 4 N, it has been described that the median lethal dose of M 4 N for mice was greater than 1,000 mg/kg while that of NDGA was only 75 mg/kg (12,14,39). Moreover, it has been reported that patients can tolerate higher doses of M 4 N with minimal side effects (15).…”

“…Nowadays, NDGA is being evaluated to treat a wide variety of illnesses, including diabetes, pain, inflammation, infertility, rheumatism, arthritis, and gallbladder and kidney stones (11,12). Remarkably, a synthetic methylated derivative of NDGA, termed tetra-O-methyl nordihydroguaiaretic acid (M 4 N, Terameprocol, or EM-1421), which retains a high similarity in the molecular structure with its precursor, is currently in phase I/II clinical trials in patients with advanced cancer (13)(14)(15). However, to our knowledge, the potential antiviral effect of M 4 N has not been assessed against any flavivirus.…”

Effect of nordihydroguaiaretic acid on spermatogenesis and fertility in rats

“…As ethanol is toxic to the testis (Cobb, Ennis, Van Thiel, Gavaler, & Lester, ), DMSO was used instead. A water‐soluble semi‐synthetic derivative of NDGA, tetra‐ O ‐methylnordihydroguaiaretic acid (terameprocol), was developed recently and can be taken orally by humans (Kimura & Huang, ). Despite differences in the pharmacokinetics of oral and i.p., routes, this study sheds light on the possible harmful effect of NDGA and its derivatives on testis.…”

“…It was demonstrated that NDGA and its semi‐synthetic derivative tetra‐ O ‐methylnordihydroguaiaretic acid (terameprocol) are effective in treating several tumours including prostate cancer (Ryan, Harzstark et al., ), breast cancer (Youngren et al., ), melanoma (Lambert, Meyers, Timmermann, & Dorr, ), lung cancer (Avis et al., ) and neuroblastoma (Meyer et al., ). Terameprocol is currently in Phase I/II clinical trials in patients with advanced cancers (Kimura & Huang, ).…”