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

Peuhu, Emilia; Paul, Preethy; Remes, Mika; Holmbom, Thomas; Eklund, Patrik; Sjöholm, Rainer; Eriksson, John E.

doi:10.1016/j.bcp.2013.05.026

Cited by 22 publications

(19 citation statements)

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“…NTG and MR) or their metabolites (e.g. enterolactone) inhibit growth of PCa cells in vitro [22], [41], but it is not known if they are effective in PCa in vivo . Stilbenoids, such as RV and pterostilbene attenuate the growth of PCa xenografts [13], [42], [43], but there is no earlier published data on PS or its analogs in PCa models in vitro or in vivo .…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, plant-derived stilbenoids, resveratrol (RV) and pterostilbene have been reported to suppress the growth of PCa in vivo [13]. Several possible mechanisms, by which lignans and stilbenoids may exert their anticarcinogenic actions in PCa have been identified, including cell cycle arrest and induction of apoptosis [14], [15], inhibition of cell proliferation [16], [17], tumor vascularization [18], modulation of cytokine profile [19], and sensitization of cancer cells to programmed cell death [20], [21], [22].…”

Section: Introductionmentioning

confidence: 99%

“…Resistance to TRAIL is common in PCa, and compounds that sensitize PCa to TRAIL are currently under active investigation. Interestingly, lignans, such as matairesinol (MR), and nortrachelogenin (NTG), as well as RV enhance the antitumor activity of TRAIL in PCa cells [21], [22] or xenografts [18].…”

Section: Introductionmentioning

confidence: 99%

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Novel Lignan and Stilbenoid Mixture Shows Anticarcinogenic Efficacy in Preclinical PC-3M-luc2 Prostate Cancer Model

et al. 2014

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Prostate cancer is the most common cancer of men in the Western world, and novel approaches for prostate cancer risk reduction are needed. Plant-derived phenolic compounds attenuate prostate cancer growth in preclinical models by several mechanisms, which is in line with epidemiological findings suggesting that consumption of plant-based diets is associated with low risk of prostate cancer. The objective of this study was to assess the effects of a novel lignan-stilbenoid mixture in PC-3M-luc2 human prostate cancer cells in vitro and in orthotopic xenografts. Lignan and stilbenoid –rich extract was obtained from Scots pine (Pinus sylvestris) knots. Pine knot extract as well as stilbenoids (methyl pinosylvin and pinosylvin), and lignans (matairesinol and nortrachelogenin) present in pine knot extract showed antiproliferative and proapoptotic efficacy at ≥40 μM concentration in vitro. Furthermore, pine knot extract derived stilbenoids enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induced apoptosis already at ≥10 μM concentrations. In orthotopic PC-3M-luc2 xenograft bearing immunocompromized mice, three-week peroral exposure to pine knot extract (52 mg of lignans and stilbenoids per kg of body weight) was well tolerated and showed anti-tumorigenic efficacy, demonstrated by multivariate analysis combining essential markers of tumor growth (i.e. tumor volume, vascularization, and cell proliferation). Methyl pinosylvin, pinosylvin, matairesinol, nortrachelogenin, as well as resveratrol, a metabolite of pinosylvin, were detected in serum at total concentration of 7−73 μM, confirming the bioavailability of pine knot extract derived lignans and stilbenoids. In summary, our data indicates that pine knot extract is a novel and cost-effective source of resveratrol, methyl pinosylvin and other bioactive lignans and stilbenoids. Pine knot extract shows anticarcinogenic efficacy in preclinical prostate cancer model, and our in vitro data suggests that compounds derived from the extract may have potential as novel chemosensitizers to TRAIL. These findings promote further research on health-related applications of wood biochemicals.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel Lignan and Stilbenoid Mixture Shows Anticarcinogenic Efficacy in Preclinical PC-3M-luc2 Prostate Cancer Model

et al. 2014

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“…It was also moderately active against HIV-1 in vitro [24]. In a recent study, nortrachelogenin was shown to enhance the tumor necrosis factor-related apoptosis-inducing ligand and to inhibit Akt signalling [25], but its anti-inflammatory potential remains practically unexplored.…”

Section: Anti-inflammatory Effects Of Nortrachelogenin In Murine J774mentioning

confidence: 99%

Anti-inflammatory Effects of Nortrachelogenin in Murine J774 Macrophages and in Carrageenan-Induced Paw Edema Model in the Mouse

et al. 2016

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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 (iNOS), cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase-1 (mPGES-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 iNOS, COX-2 and mPGES-1 as well as on the production of nitric oxide (NO), prostaglandin E2 (PGE2) and cytokines IL-6 and MCP-1 were investigated in 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 NO, PGE2, IL-6 and MCP-1 in J774 macrophages in vitro.Nortrachelogenin inhibited mPGES-1 protein expression but had no effect on COX-2 protein levels.Nortrachelogenin had also a clear inhibitory effect on iNOS protein expression but none on iNOS mRNA levels, and the proteasome inhibitor lactacystin reversed the effect of nortrachelogenin on iNOS 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.

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“…Thereby, several works have investigated the potential applications of pine knot or its main constituents for their health‐promoting properties on humans. Pine knot extracts have notably shown anticarcinogenic and anti‐inflammatory activities , attributing this effect to the presence of the lignan nortrachelogenin , the flavonoids pinocembrin and pinobanksin , as well as the pinosylvins . Moreover, other studies have shown potent antimicrobial, antifungal, and oomycide properties by pine knot extracts .…”

Section: Introductionmentioning

confidence: 99%

Separation and isolation of major polyphenols from maritime pine (Pinus pinaster) knots by two‐step centrifugal partition chromatography monitored by LC‐MS and NMR spectroscopy

Gabaston

Leborgne

Waffo-Téguo

et al. 2020

J of Separation Science

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Pine knots are a rich source of lignans, flavonoids, and stilbenes. These bioactive compounds are widely known for their roles to combat human disorders but also to protect plants against pathogens. In order to gain knowledge inside their potential activities, a suitable isolation and purification of these high‐added value compounds is required. To this end, centrifugal partition chromatography, as a rapid and useful methodology of separation, was employed and developed. The coefficient partition values (KD) of six major compounds in nine biphasic solvent systems were determined to evaluate the most appropriate system. Two‐step centrifugal partition chromatography was required to separate lignans using ARIZONA system K (n‐heptane/ethyl acetate/methanol/water 1:2:1:2, v:v) and to isolate stilbenes and flavonoids using ARIZONA system P (n‐heptane/ethyl acetate/methanol/water 6:5:6:5, v:v). Eight one‐compound enriched‐fractions were obtained as follows: nortrachelogenin (70.1%), secoisolariciresinol (53.7%), isolariciresinol (61.1%), taxifolin (48.4%), pinocembrin (91.3%), pinobanksin (91.1%), pinosylvin (91.4%), and pinosylvin monomethyl ether (91.1%). Additionally, the centrifugal partition chromatography allowed to unravel the composition of pine knot owing to the several fractions generated. Twenty‐two compounds were characterized by liquid chromatography‐mass spectrometry and NMR spectroscopy, some of which are described for the first time in literature.

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

Cited by 22 publications

References 53 publications

Novel Lignan and Stilbenoid Mixture Shows Anticarcinogenic Efficacy in Preclinical PC-3M-luc2 Prostate Cancer Model

Novel Lignan and Stilbenoid Mixture Shows Anticarcinogenic Efficacy in Preclinical PC-3M-luc2 Prostate Cancer Model

Anti-inflammatory Effects of Nortrachelogenin in Murine J774 Macrophages and in Carrageenan-Induced Paw Edema Model in the Mouse

Separation and isolation of major polyphenols from maritime pine (Pinus pinaster) knots by two‐step centrifugal partition chromatography monitored by LC‐MS and NMR spectroscopy

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