title: The drug vehicle and solvent N-methylpyrrolidone is an immunomodulator and antimyeloma compound.
abstract: N-methyl-2-pyrrolidone (NMP) is a common solvent and drug vehicle. We discovered unexpected antineoplastic and immunomodulatory activity of NMP in a cMYC-driven myeloma model. Coincident to this, NMP was identified as an acetyllysine mimetic and candidate bromodomain ligand. Accordingly, NMP-treated cells demonstrated transcriptional overlap with BET-bromodomain inhibition, including downregulation of cMYC and IRF4. NMP's immunomodulatory activity occurred at sub-BET inhibitory concentrations, and, despite phenotypic similarities to lenalidomide, its antimyeloma activity was independent of the IMiD targets cereblon and Ikaros-1/3. Thus, low-affinity yet broad-spectrum bromodomain inhibition by NMP mediates biologically potent, cereblon-independent immunomodulation and at higher doses targets malignant cells directly via BET antagonism. These data reveal that NMP is a functional acetyllysine mimetic with pleotropic antimyeloma and immunomodulatory activities. Our studies highlight the potential therapeutic benefits of NMP, the consequences of current human NMP exposures, and the need for reassessment of scientific literature where NMP was used as an "inert" drug-delivery vehicle.
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Andy K
authors.initials: AK
authors.lastname: Hsu
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Martin
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
authors.forename: Karen
authors.initials: K
authors.lastname: Doggett
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Matthews
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Doyle
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Tina E
authors.initials: TE
authors.lastname: Jockel
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Andrews
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Hogg
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Reitsma
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Faulkner
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ 85259, USA.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ 85259, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.affiliation: Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
authors.forename: Joan K
authors.initials: JK
authors.lastname: Heath
authors.affiliation: Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand.
authors.forename: William A
authors.initials: WA
authors.lastname: Denny
authors.affiliation: Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thompson
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Neeson
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: David S
authors.initials: DS
authors.lastname: Ritchie
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia.
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.affiliation: Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC 3002, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3002, Australia. Electronic address: ricky.johnstone@petermac.org.
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011760:Pyrrolidinones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007155:Immunologic Factors; D011760:Pyrrolidinones; C038678:N-methylpyrrolidone