title: Dll1/Notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma.
abstract: One of the greatest challenges in multiple myeloma (MM) treatment is to overcome drug resistance. Many pathways are involved including Notch signaling. Notch receptors are expressed by MM cells and Notch ligand Dll1 is present on bone marrow (BM) stromal cells. In this study, we demonstrate that Dll1 can activate Notch signaling mostly through Notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human MM cells. Blocking the Notch pathway by DAPT (gamma secretase inhibitor) could reverse this effect and increased sensitivity to bortezomib. We describe the upregulation of CYP1A1, a Cytochrome P450 enzyme involved in drug metabolism, as a possible mechanism of Dll1/Notch induced bortezomib resistance. This was confirmed by inhibition experiments using α-Naphthoflavone or CYP1A1-siRNA that resulted in an increased sensitivity to bortezomib. In addition, in vivo data showed that combination treatment of DAPT with bortezomib was able to increase bortezomib sensitivity and prolonged overall survival in the 5T33MM mouse model. Our data provide a potential strategy to overcome bortezomib resistance by Notch inhibition in MM therapy.
authors.affiliation: Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Dehui
authors.initials: D
authors.lastname: Xu
authors.forename: Jinsong
authors.initials: J
authors.lastname: Hu
authors.forename: Elke
authors.initials: E
authors.lastname: De Bruyne
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
authors.forename: Rik
authors.initials: R
authors.lastname: Schots
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001571:Benzoflavones / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000819:agonists*; D008565:Membrane Proteins / Q000819:agonists*; D051379:Mice; D009101:Multiple Myeloma / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D051880:Receptors, Notch / Q000819:agonists*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001571:Benzoflavones; D001897:Boronic Acids; D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011719:Pyrazines; D051880:Receptors, Notch; C011512:alpha-naphthoflavone; D000069286:Bortezomib; D019363:Cytochrome P-450 CYP1A1