The novel, proteasome-independent NF-kappaB inhibitor V1810 induces apoptosis and cell cycle arrest in multiple myeloma and overcomes NF-kappaB-mediated drug resistance

Molecular Cancer Therapeutics
Felix G MeinelRalf Schmidmaier

Abstract

Evidence is increasing that aberrant NF-kappaB activation is crucial for multiple myeloma pathophysiology and a promising target for new antimyeloma therapies. In this study, we assessed the in vitro antimyeloma activity of the novel NF-kappaB inhibitor V1810. Pharmacokinetics and toxicity were studied in vivo. In mice, V1810 plasma concentrations of 10 micromol/L can be reached without relevant toxicity. At this concentration, V1810 potently induces apoptosis in all four multiple myeloma cell lines assessed (IC(50) = 5-12 micromol/L) as well as in primary multiple myeloma cells (IC(50) = 5-40 micromol/L). Apoptosis induced by V1810 is associated with proteasome-independent inhibition of NF-kappaB signaling (41% relative reduction), downregulation of Mcl-1, and caspase 3 cleavage. In OPM2, U266, and RPMI-8226 cells, induction of apoptosis is accompanied by cell cycle arrest. Western blots revealed downregulation of Cdk4 as well as cyclin D1 (U266) or cyclin D2 (OPM2, NCI-H929, RPMI-8226), but not cyclin D3. Consistently, retinoblastoma protein was found to be hypophosphorylated. Furthermore, V1810 reverses NF-kappaB activation induced by the genotoxic drugs melphalan and doxorubicin. V1810 and melphalan synergistically decrease...Continue Reading

References

Apr 5, 1996·The Journal of Biological Chemistry·E S Knudsen, J Y Wang
May 9, 1997·The Journal of Biological Chemistry·T Zarkowska, S Mittnacht
Sep 28, 1999·Oncogene·M F Roussel
Sep 22, 2001·The Journal of Biological Chemistry·J F KurlandR E Meyn
Dec 12, 2001·Seminars in Oncology·J R BerensonR Vescio
Jul 9, 2003·Immunological Reviews·P Leif Bergsagel, W Michael Kuehl
Apr 20, 2004·Blood·Teru HideshimaKenneth C Anderson
Nov 4, 2004·International Journal of Cancer. Journal International Du Cancer·Mariko WatanabeRyouichi Horie
Nov 16, 2004·Cancer Cell·Constantine S MitsiadesKenneth C Anderson
Mar 10, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Takaomi SandaTakashi Okamoto
Apr 14, 2005·Molecular Cancer Therapeutics·Dharminder ChauhanKenneth C Anderson
Sep 13, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·P Leif Bergsagel, W Michael Kuehl
Jul 6, 2006·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Martin KropffJoachim Kienast
Oct 6, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Teru HideshimaKenneth C Anderson
Jun 5, 2007·British Journal of Haematology·Michel JourdanBernard Klein
Jul 3, 2007·The Oncologist·Paul G RichardsonKenneth Anderson
Aug 19, 2007·Cancer Cell·Thomas D Gilmore
Aug 19, 2007·Cancer Cell·Jonathan J KeatsP Leif Bergsagel
Sep 18, 2007·Bioorganic & Medicinal Chemistry Letters·Johann LebanMarkus H J Seifert
Dec 18, 2007·Leukemia Research·Philipp BaumannRalf Schmidmaier
Feb 13, 2008·Cell·Matthew S Hayden, Sankar Ghosh
Apr 9, 2008·Current Medicinal Chemistry·R Schmidmaier, P Baumann
Aug 19, 2008·Molecular Cancer Research : MCR·Stephanie MarkovinaShigeki Miyamoto
Jan 17, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Guido BispingJoachim Kienast

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Citations

Nov 3, 2015·Expert Review of Anticancer Therapy·Maria MoschoviSpiros Vlahopoulos
Sep 10, 2013·Surgical Oncology Clinics of North America·Derek J Erstad, James C Cusack
Jan 10, 2013·PloS One·Diana MarkleinHeidi Hahn
Nov 28, 2012·PloS One·Verena SchoewelSimone Spuler
Sep 11, 2012·Molecular Cell·Amila SuraweeraAnne Bertolotti
Sep 5, 2012·Critical Reviews in Oncology/hematology·L H A M de WiltF A E Kruyt
Sep 13, 2014·Hematology/oncology Clinics of North America·Cindy VargaPaul G Richardson
Jan 1, 2014·Antiviral Research·Yannick Debing, Johan Neyts
Dec 27, 2011·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Firoozeh SahebiStephen J Forman
Dec 21, 2010·Current Opinion in Cell Biology·Simone CenciRoberto Sitia
Nov 22, 2016·International Journal of Molecular Sciences·Bingqian XieWeiliang Zhu
Mar 8, 2013·The Journal of Chemical Physics·Jeffrey K Weber, Vijay S Pande
Oct 26, 2018·Laboratory Investigation; a Journal of Technical Methods and Pathology·Masanobu TsubakiShozo Nishida
Sep 27, 2012·Molecular Cancer Therapeutics·Yuji ShimuraMasafumi Taniwaki

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