BACKGROUND AND PURPOSE: Follicular lymphoma is the second most common non-Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems. EXPERIMENTAL APPROACH: The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment. KEY RESULTS: Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3β. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice. CONCLUSIONS AND IMPLICATIONS: The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.
BACKGROUND AND PURPOSE:Follicular lymphoma is the second most common non-Hodgkin's lymphoma and, despite the introduction of rituximab for its treatment, this disease is still considered incurable. Besides genetic alterations involving Bcl-2, Bcl-6 or c-Myc, follicular lymphoma cells often display altered B-cell receptor signalling pathways including overactive PKC and PI3K/Akt systems. EXPERIMENTAL APPROACH: The effect of enzastaurin, an inhibitor of PKC, was evaluated both in vitro on follicular lymphoma cell lines and in vivo on a xenograft murine model. Using pharmacological inhibitors and siRNA transfection, we determined the different signalling pathways after enzastaurin treatment. KEY RESULTS:Enzastaurin inhibited the serine-threonine kinase p90RSK which has downstream effects on GSK3β. Bad and p70S6K. These signalling proteins control follicular lymphoma cell survival and apoptosis; which accounted for the inhibition by enzastaurin of cell survival and its induction of apoptosis of follicular lymphoma cell lines in vitro. Importantly, these results were replicated in vivo where enzastaurin inhibited the growth of follicular lymphoma xenografts in mice. CONCLUSIONS AND IMPLICATIONS: The targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.
Authors: Margaret A Shipp; Ken N Ross; Pablo Tamayo; Andrew P Weng; Jeffery L Kutok; Ricardo C T Aguiar; Michelle Gaasenbeek; Michael Angelo; Michael Reich; Geraldine S Pinkus; Tane S Ray; Margaret A Koval; Kim W Last; Andrew Norton; T Andrew Lister; Jill Mesirov; Donna S Neuberg; Eric S Lander; Jon C Aster; Todd R Golub Journal: Nat Med Date: 2002-01 Impact factor: 53.440
Authors: Christian Gulmann; Virginia Espina; Emanuel Petricoin; Dan L Longo; Mariarita Santi; Turid Knutsen; Mark Raffeld; Elaine S Jaffe; Lance A Liotta; Andrew L Feldman Journal: Clin Cancer Res Date: 2005-08-15 Impact factor: 12.531
Authors: Philippe P Roux; Bryan A Ballif; Rana Anjum; Steven P Gygi; John Blenis Journal: Proc Natl Acad Sci U S A Date: 2004-09-01 Impact factor: 11.205
Authors: Hongbin Zha; Mark Raffeld; Lu Charboneau; Stefania Pittaluga; Larry W Kwak; Emanuel Petricoin; Lance A Liotta; Elaine S Jaffe Journal: Lab Invest Date: 2004-02 Impact factor: 5.662