title: Combined administration of rituximab and on 013105 induces apoptosis in mantle cell lymphoma cells and reduces tumor burden in a mouse model of mantle cell lymphoma.
abstract: OBJECTIVE
  Mantle cell lymphoma (MCL) is an incurable B-cell lymphoma, and new therapeutic strategies are urgently needed.
  
  
  METHODS
  The effects of ON 013105, a novel benzylstyryl sulfone kinase inhibitor, alone or with doxorubicin or rituximab, were examined in Granta 519 and Z138C cells. For in vivo studies, CB17/SCID mice were implanted subcutaneously with Z138C cells and treated with various combinations of ON 013105, doxorubicin, and rituximab. Tumor burden and body weight were monitored for 28 days.
  
  
  RESULTS
  ON 013105 induced mitochondria-mediated apoptosis in MCL cells. Death was preceded by translocation of tBid to the mitochondria and cytochrome c release. In addition, ON 013105-treated cells exhibited reduced levels of cyclin D1, c-Myc, Mcl-1, and Bcl-xL. Using nuclear magnetic resonance (NMR) spectroscopy, we showed specific binding of ON 013105 to eIF4E, a critical factor for the initiation of protein translation. We proffer that this drug-protein interaction preferentially prevents the translation of the aforementioned proteins and may be the mechanism by which ON 013105 induces apoptosis in MCL cells. Efficacy studies in a mouse xenograft model showed that ON 013105 inhibited MCL tumor growth and that combining ON 013105 with rituximab reduced tumor burden further with negligible unwanted effects.
  
  
  CONCLUSIONS
  Our findings suggest that ON 013105, alone or in combination with rituximab, may be a potent therapeutic agent to treat MCLs.
authors.affiliation: Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Prasad
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Shrivastava
authors.forename: Evangelos
authors.initials: E
authors.lastname: Papadopoulos
authors.forename: Paula M
authors.initials: PM
authors.lastname: Kuzontkoski
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Gillum
authors.forename: Ramesh
authors.initials: R
authors.lastname: Kumar
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
authors.forename: Jerome E
authors.initials: JE
authors.lastname: Groopman
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D000069283:Rituximab; D013343:Styrenes / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D013450:Sulfones / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D058846:Antibodies, Monoclonal, Murine-Derived; D039561:Eukaryotic Initiation Factor-4E; C581702:ON 013105; D016271:Proto-Oncogene Proteins c-myc; D013343:Styrenes; D013450:Sulfones; D019938:Cyclin D1; D000069283:Rituximab; D004317:Doxorubicin