title: Novel treatment for mantle cell lymphoma including therapy-resistant tumor by NF-κB and mTOR dual-targeting approach.
abstract: Mantle cell lymphoma (MCL) is one of the most aggressive B-cell non-Hodgkin lymphomas with a median survival of approximately five years. Currently, there is no curative therapy available for refractory MCL because of relapse from therapy-resistant tumor cells. The NF-κB and mTOR pathways are constitutively active in refractory MCL leading to increased proliferation and survival. Targeting these pathways is an ideal strategy to improve therapy for refractory MCL. Therefore, we investigated the in vitro and in vivo antilymphoma activity and associated molecular mechanism of action of a novel compound, 13-197, a quinoxaline analog that specifically perturbs IκB kinase (IKK) β, a key regulator of the NF-κB pathway. 13-197 decreased the proliferation and induced apoptosis in MCL cells including therapy-resistant cells compared with control cells. Furthermore, we observed downregulation of IκBα phosphorylation and inhibition of NF-κB nuclear translocation by 13-197 in MCL cells. In addition, NF-κB-regulated genes such as cyclin D1, Bcl-XL, and Mcl-1 were downregulated in 13-197-treated cells. In addition, 13-197 inhibited the phosphorylation of S6K and 4E-BP1, the downstream molecules of mTOR pathway that are also activated in refractory MCL. Further, 13-197 reduced the tumor burden in vivo in the kidney, liver, and lungs of therapy-resistant MCL-bearing nonobese diabetic severe-combined immunodeficient (NOD/SCID) mice compared with vehicle-treated mice; indeed, 13-197 significantly increased the survival of MCL-transplanted mice. Together, results suggest that 13-197 as a single agent disrupts the NF-κB and mTOR pathways leading to suppression of proliferation and increased apoptosis in malignant MCL cells including reduction in tumor burden in mice.
authors: Corresponding Author: Shantaram S. Joshi, Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, 986395 Nebraska Medical Center, Omaha, NE 68198-6395. ssjoshi@unmc.edu.
authors: Nagendra K
authors: NK
authors: Chaturvedi
authors: Rajkumar N
authors: RN
authors: Rajule
authors: Ashima
authors: A
authors: Shukla
authors: Prakash
authors: P
authors: Radhakrishnan
authors: Gordon L
authors: GL
authors: Todd
authors: Amarnath
authors: A
authors: Natarajan
authors: Julie M
authors: JM
authors: Vose
authors: Shantaram S
authors: SS
authors: Joshi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis / Q000235:genetics*; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011810:Quinoxalines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D023041:Xenograft Model Antitumor Assays
chemical_list: C584232:13-197 compound; D016328:NF-kappa B; D010671:Phenylurea Compounds; D011810:Quinoxalines; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase
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