Nortrachelogenin

The antitumor lignan Nortrachelogenin sensitizes prostate cancer cells to TRAIL-induced cell death by inhibition of the Akt pathway and growth factor signaling.[Pubmed:23747345]

Biochem Pharmacol. 2013 Sep 1;86(5):571-83.

Prostate cancer cells frequently develop resistance toward androgen-deprivation and chemotherapy. To identify new approaches to treat androgen-dependent prostate cancer, we have performed a structure-activity analysis of lignan polyphenols for cancer cell specific sensitization to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a death ligand that has ability to induce tumor-specific cell death. In this study, we report that the lignan Nortrachelogenin (NTG) is the most efficient of the 27 tested lignan compounds in sensitizing prostate cancer cells to TRAIL-induced apoptosis. Importantly, pretreatment with NTG does not sensitize a non-malignant prostate cell line to TRAIL-induced cell death. The structural comparison of lignans reveals that the dibenzylbutyrolactone skeleton is required for the apoptosis-sensitizing activity, while substitutions at the aromatic rings do not seem to play a critical role in this lignan function. Our study also characterizes the cellular effects and molecular mechanisms involved in NTG anticancer activity. We previously reported that specific lignans inhibit the Akt survival-signaling pathway in concert with TRAIL sensitization. While NTG is also shown to be a effective inhibitor of Akt signaling, in this study we further demonstrate that NTG potently inhibits tyrosine kinase (RTK) activation in response to growth factors, such as insulin and insulin-like growth factor I (IGF-I). Our results identify NTG as a novel agent for prostate cancer therapy with ability to inhibit Akt membrane localization and activity as well as the activation of growth factor receptors (GFRs), thereby efficiently synergizing with TRAIL exposure.

Anti-inflammatory Effects of Nortrachelogenin in Murine J774 Macrophages and in Carrageenan-Induced Paw Edema Model in the Mouse.[Pubmed:27737478]

Planta Med. 2017 Apr;83(6):519-526.

Nortrachelogenin is a pharmacologically active lignan found in knot extracts of Pinus sylvestris. In previous studies, some lignans have been shown to have anti-inflammatory properties, which made Nortrachelogenin an interesting candidate for our study. In inflammation, bacterial products and cytokines induce the expression of inducible nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E synthase-1. These enzymes synthesize factors, which, together with proinflammatory cytokines, are important mediators and drug targets in inflammatory diseases.The effects of Nortrachelogenin on the expression of inducible nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E synthase-1 as well as on the production of nitric oxide, prostaglandin E2, and cytokines interleukin-6 and monocyte chemotactic protein-1 were investigated in the murine J774 macrophage cell line. In addition, we examined the effect of Nortrachelogenin on carrageenan-induced paw inflammation in mice.Interestingly, Nortrachelogenin reduced carrageenan-induced paw inflammation in mice and inhibited the production of inflammatory factors nitric oxide, prostaglandin E2, interleukin-6, and monocyte chemotactic protein-1 in J774 macrophages in vitro. Nortrachelogenin inhibited microsomal prostaglandin E synthase-1 protein expression but had no effect on cyclooxygenase-2 protein levels. Nortrachelogenin also had a clear inhibitory effect on inducible nitric oxide synthase protein expression but none on its mRNA levels, and the proteasome inhibitor lactacystin reversed the effect of Nortrachelogenin on inducible nitric oxide synthase expression, suggesting a post-transcriptional mechanism of action.The results revealed hitherto unknown anti-inflammatory properties of Nortrachelogenin, which could be utilized in the development of anti-inflammatory treatments.

(-)-Nortrachelogenin from Partrinia scabiosaefolia elicits an apoptotic response in Candida albicans.[Pubmed:26880798]

FEMS Yeast Res. 2016 May;16(3). pii: fow013.

This study analyzes the antifungal properties of (-)-Nortrachelogenin and elucidates its mode of action against pathogenic fungi. We performed susceptibility tests against several pathogenic fungi and verified the absence of hemolysis against human erythrocytes. Its antifungal activity increased reactive oxygen species (ROS) in response to intracellular stress and increased concentrations of both intracellular and extracellular trehalose without causing hemolysis. In addition, a cell wall regeneration study indicated its action on the cytoplasmic membrane. A cell surface study using 3,3(')-dipropylthiacarbocyanine iodide [DiSC3(5)] and 1,6-diphenyl-1,3,5-hexatriene (DPH) demonstrated dissipation of the cytoplasmic membrane at high concentrations. Our study revealed a disturbance in the membrane at higher concentrations and externalization of phosphatidylserine in a dose-dependent manner, affecting other intracellular responses. Furthermore, we investigated the late stage of apoptosis using TUNEL and 4('),6-diamidino-2-phenylindole (DAPI) assays. (-)-Nortrachelogenin-treated cells underwent apoptosis which was triggered by mitochondrial dysfunction via depolarization of the mitochondrial membrane, release of cytochrome c and calcium ion signaling, resulting in the activation of metacaspases. Different concentrations of (-)-Nortrachelogenin induced membrane disruption and caspase-dependent apoptosis.

(+)-Nortrachelogenin, a new pharmacologically active lignan from Wikstroemia indica.[Pubmed:501363]

J Nat Prod. 1979 Mar-Apr;42(2):159-62.

A new lignan, (+)-Nortrachelogenin (I), and a known compound, daphnoretin were isolated from Wikstroemia indica C. A. Meyer (Thymelaeaceae). The structure of (+)-Nortrachelogenin was established as 8(R), 8'(R)-4,4',8'-trihydroxy-3,3'-dimethoxylignan-olid(9, 9') on the basis of spectroscopic evidence and comparison with its enantiomer, (-)-Nortrachelogenin. (+)-Nortrachelogenin (I) showed effects on the central nervous system producing depression in rabbits.

Antifungal, antimitotic and anti-HIV-1 agents from the roots of Wikstroemia indica.[Pubmed:10985087]

Planta Med. 2000 Aug;66(6):564-7.

With guidance of Pyricularia oryzae bioassay, daphnoretin (1), (+)-Nortrachelogenin (2), genkwanol A (3), wikstrol A (4), wikstrol B (5) and daphnodorin B (6) were isolated from the roots of Wikstroemia indica. Compounds 1-6 induced morphological deformation of P. oryzae mycelia with MMDC values of 68.4 +/- 1.3, 31.3 +/- 1.8, 45.8 +/- 0.5, 70.1 +/- 2.4, 52.3 +/- 0.9 and 73.7 +/- 1.6 microM, respectively. Compounds 3-6 showed moderate activity against microtubule polymerization with IC50 values of 112 +/- 4, 131 +/- 3, 184 +/- 6 and 142 +/- 2 microM in vitro, respectively. Compounds 2, 3, 5 and 6 were moderately active against HIV-1 in vitro. The findings of bioactivity of 1-6 support the antifungus, antimitosis and anti-HIV-1 uses for W. indica roots.

Antibacterial Mechanism of (-)-Nortrachelogenin in Escherichia coli O157.[Pubmed:26420306]

Curr Microbiol. 2016 Jan;72(1):48-54.

(-)-Nortrachelogenin is a lignan belonging to group of polyphenolic compounds. Its biological properties in mammalian cells are well-studied; however, its biological effects in microorganisms remain poorly understood. Its efficacy against pathogenic bacteria, including antibiotic-resistant strains, was investigated and it was found that bacteria are highly susceptible to the antibacterial effects of this compound. To investigate the antibacterial mode of action(s) against Escherichia coli O157, its effect on the penetration of SYTOX green into bacterial cells was assayed. The penetration of SYTOX Green into a bacterial cell is a measure of permeability of the plasma membrane. An increase in fluorescence intensity using bis-(1,3-dibutylbarbituric acid) trimethine oxonol [DiBAC4(3)] and 3,3'-dipropylthiacarbocyanine iodide [DiSC3(5)] was also observed, indicating membrane depolarization. Potassium ion efflux from the cytosol into the extracellular matrix showed that cellular damage due to (-)-Nortrachelogenin treatment resulted in the loss of intracellular components. While cells were damaged by (-)-Nortrachelogenin, large unilamellar vesicles containing fluorescein isothiocyanate-dextran were perturbed to migrate molecules between 3.3 and 4.8 nm. The release of calcein from giant unilamellar vesicles, occurring as a result of disruption in artificial membranes, was visualized. Taken together, our results indicate that (-)-Nortrachelogenin exerts its antibacterial effect by disorganizing and perturbing the cytoplasmic membrane, demonstrating the potential of this compound as a candidate for antibiotic drug development.