title: A novel inhibitor of focal adhesion signaling induces caspase-independent cell death in diffuse large B-cell lymphoma.
abstract: Focal adhesion (FA) proteins have been associated with transformation, migration, metastasis, and poor outcome in many neoplasias. We previously showed that these proteins were inhibited by E7123, a new celecoxib derivative with antitumor activity, in acute myeloid leukemia. However, little is known about FAs in diffuse large B cell lymphoma (DLBCL). This paper aimed to determine whether E7123 was effective against DLBCL and whether FAs were involved in its action. We evaluated the cytotoxicity and mechanism of action of E7123 and celecoxib in DLBCL cell lines. We also assessed the E7123 in vivo activity in a DLBCL xenograft model and studied FA signaling in primary DLBCL patient samples. We found that E7123 showed higher antitumor effect than celecoxib against DLBCL cells. Its mechanism of action involved deregulation of FA, AKT, and Mcl-1 proteins, a pathway that is activated in some patient samples, apoptosis-inducing factor release and induction of caspase-independent cell death. Moreover, E7123 showed suppression of in vivo tumor growth. These findings indicate that E7123 is effective against DLBCL in vitro and in vivo, with a mechanism of action that differs from that of most current therapies for this malignancy. Our results support further preclinical evaluation of E7123.
authors.affiliation: Grup d'Oncogènesi i Antitumorals, lnstitut d'Investigacions Biomèdiques Sant Pau, Barcelona, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bosch
authors.forename: Rebeca
authors.initials: R
authors.lastname: Dieguez-Gonzalez
authors.forename: Maria Virtudes
authors.initials: MV
authors.lastname: Céspedes
authors.forename: Matilde
authors.initials: M
authors.lastname: Parreño
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Pavón
authors.forename: Albert
authors.initials: A
authors.lastname: Grañena
authors.forename: Jorge
authors.initials: J
authors.lastname: Sierra
authors.forename: Ramon
authors.initials: R
authors.lastname: Mangues
authors.forename: Isolda
authors.initials: I
authors.lastname: Casanova
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020169:Caspases / Q000378:metabolism; D000068579:Celecoxib; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D050719:Crk-Associated Substrate Protein / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D022001:Focal Adhesions / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D020169:Caspases; D000068579:Celecoxib; D050719:Crk-Associated Substrate Protein; D052246:Cyclooxygenase 2 Inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D013449:Sulfonamides; C529090:4-(5-(2,5-dimethylphenyl)-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C579094:Mcl1 protein, mouse