• S Kheirallah, S Fruchon, L Ysebaert, A Blanc, F Capilla, A Marrot, T Alsaati, F X Frenois, K A Benhadji, J J Fournié, G Laurent, and C Bezombes.
• INSERM UMR1037-Centre de Recherche en Cancérologie de Toulouse, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France; ERL 5294 CNRS, BP3028, Hôpital Purpan, Toulouse, France; Institut Carnot Lymphome-CALYM, Toulouse, France; Laboratoire d'Excellence Toulouse Cancer-TOUCAN, Toulouse, France.
• Br. J. Pharmacol. 2013 Dec 1; 170 (7): 1374-83.

Background And PurposeFollicular 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 ApproachThe 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 ResultsEnzastaurin 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 ImplicationsThe targeting of p90RSK by enzastaurin represents a new therapeutic option for the treatment of follicular lymphoma.© 2013 The British Pharmacological Society.

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