The Drug Vehicle and Solvent N-Methylpyrrolidone Is an Immunomodulator and Antimyeloma Compound

Shortt, Jake; Hsu, Andy; Martin, Benjamin P.; Doggett, Karen; Matthews, Geoffrey M.; Doyle, Maria A.; Ellul, Jason; Jockel, Tina E.; Andrews, Daniel M.; Hogg, Simon J.; Reitsma, Andrea; Faulkner, David; Bergsagel, P. Leif; Chesi, Marta; Heath, Joan K.; Denny, William A.; Thompson, Phillip E.; Neeson, Paul J.; Ritchie, David; McArthur, Grant A.; Johnstone, Ricky W.

doi:10.1016/j.celrep.2014.04.008

Cited by 33 publications

(40 citation statements)

References 39 publications

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“…Due to this characteristic, NMP can be considered a low affinity bromodomain inhibitor. These results are consistent with the recently published data showing that NMP is a functional acetyl lysine mimetic molecule [17,27].…”

Section: Discussionsupporting

confidence: 83%

The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

Gjoksi

Ghayor

Siegenthaler

et al. 2015

Bone

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Currently, there are several treatments for osteoporosis however; they all display some sort of limitation and/or side effects making the need for new treatments imperative. We have previously demonstrated that NMP is a bioactive drug which enhances bone regeneration in vivo and acts as an enhancer of bone morphogenetic protein (BMP) in vitro. NMP also inhibits osteoclast differentiation and attenuates bone resorption. In the present study, we tested NMP as a bromodomain inhibitor and for osteoporosis prevention on ovariectomized (OVX) induced rats while treated systemically with NMP. Female Sprague-Dawley rats were ovariectomized and weekly NMP treatment was administrated 1 week after surgery for 15 weeks. Bone parameters and related serum biomarkers were analyzed. 15 weeks of NMP treatment decreased ovariectomy-induced gained weight in average by 43% and improved bone mineral density (BMD) and bone volume over total volume (BV/TV) in rat femur on average by 25% and 41% respectively. Moreover, mineral apposition rate and bone biomarkers of bone turnover in the treatment group were at similar levels with those of the Sham group. Due to the function of NMP as a low affinity bromodomain inhibitor and its mechanism of action involving osteoblasts/osteoclasts balance and inhibitory effect on inflammatory cytokines, NMP is a promising therapeutic compound for the prevention of osteoporosis. In the present study, we tested NMP as a bromodomain inhibitor and for osteoporosis prevention on ovariectomized (OVX) induced rats while treated systemically with NMP. Female Sprague-Dawley rats were ovariectomized and weekly NMP treatment was administrated 1 week after surgery for 15 weeks. Bone parameters and related serum biomarkers were analyzed. 15 weeks of NMP treatment decreased ovariectomy-induced gained weight in average by 43% and improved bone mineral density (BMD) and bone volume over total volume (BV/TV) in rat femur in average by 25% and 41% respectively. Moreover, mineral apposition rate and bone biomarkers of bone turnover in the treatment group were at similar levels with those of the Sham group.Due to the function of NMP as a low affinity bromodomain inhibitor and its mechanism of action involving osteoblasts/osteoclasts balance and inhibitory effect on inflammatory cytokines, NMP is a promising therapeutic compound for the prevention of osteoporosis.

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Section: Discussionsupporting

confidence: 83%

The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

Gjoksi

Ghayor

Siegenthaler

et al. 2015

Bone

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“…Our result is in line with recently published paper showing that NMP possess an immunomodulatory activity [29].…”

Section: Discussionsupporting

confidence: 83%

“…In fact, Shortt at al. showed that NMP is a functional lysine mimetic molecule [29]. Moreover, JQ1 a potent inhibitor of BRD2, BRD3, BRD4 and BET, was shown to suppress inflammation by a reduction of the inflammatory cytokine release and bone destruction by the inhibition of osteoclast maturation [30].…”

Section: Discussionmentioning

confidence: 99%

N-methyl pyrrolidone (NMP) inhibits lipopolysaccharide-induced inflammation by suppressing NF-κB signaling

et al. 2015

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OBJECTIVE: N-methyl pyrrolidone (NMP), a small bioactive molecule, stimulates bone formation and inhibits osteoclast differentiation and bone resorption. The present study was aimed to evaluate the anti-inflammatory potentials of NMP on the inflammatory process and the underlying molecular mechanisms in RAW264.7 macrophages. MATERIALS AND METHODS: RAW264.7 macrophages and mouse primary bone marrow macrophages (mBMMs) were used as an in vitro model to investigate inflammatory processes. Cells were pre-treated with or without NMP and then stimulated with lipopolysaccharides (LPS). The productions of cytokines and NO were determined by proteome profiler method and nitrite analysis, respectively. The expressions of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were measured by Western blotting and/or qPCR. Western blot, ELISA-base reporter assay, and immunofluorescence were used to evaluate the activation of MAP kinases and NF-B. RESULTS: LPS-induced mRNA expressions of TNF-, IL-1, IL-6, iNOS, and COX-2 were inhibited by NMP in a dose-dependent manner. NMP also suppressed the LPS-increased productions of iNOS and NO. The proteome profiler array showed that several cytokines and chemokines involved in inflammation and up-regulated by LPS stimulation were significantly down-regulated by NMP. Additionally, this study shows that the effect of NMP is mediated through down-regulation of NFB pathway. CONCLUSIONS: Our results show that NMP inhibits the inflammatory mediators in macrophages by an NFB-dependent mechanism, based on the epigenetical activity of NMP as bromodomain inhibitor. In the light of its action on osteoblast and osteoclast differentiation process and its anti-inflammatory potential, NMP might be used in inflammation-related bone loss. CONCLUSIONS:Our results show that NMP inhibits the inflammatory mediators in macrophages by an NFκB-dependent mechanism, based on the epigenetical activity of NMP as bromodomain inhibitor. In the light of its action on osteoblast and osteoclast differentiation process and its anti-inflammatory potential, NMP might be used in inflammation-related bone loss.

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“…It has been reported that this common laboratory solvent can act as a weak affinity, broad spectrum bromodomain inhibitor with binding demonstrated to multiple bromodomains including BET. In a mouse model of myeloma, treatment with NMP demonstrated antineoplastic and immunomodulatory activity consistent with BET inhibition [21].…”

Section: Bet Bromodomain Inhibitors In Clinical Trialsmentioning

confidence: 94%

Clinical progress and pharmacology of small molecule bromodomain inhibitors

Theodoulou¹,

Tomkinson

Prinjha

et al. 2016

Current Opinion in Chemical Biology

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Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. The excitement centred on the clinical potential of BET inhibition has stimulated intense interest in the broader family and the growing number of non-BET bromodomain chemical probes has facilitated phenotypic investigations, implicating these targets in a variety of disease pathways including cancer, inflammation, embryonic development and neurological disorders.

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The Drug Vehicle and Solvent N-Methylpyrrolidone Is an Immunomodulator and Antimyeloma Compound

Cited by 33 publications

References 39 publications

The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

N-methyl pyrrolidone (NMP) inhibits lipopolysaccharide-induced inflammation by suppressing NF-κB signaling

Clinical progress and pharmacology of small molecule bromodomain inhibitors

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