Induction of apoptosis using inhibitors of lysophosphatidic acid acyltransferase-beta and anti-CD20 monoclonal antibodies for treatment of human non-Hodgkin's lymphomas.

ABSTRACT

PURPOSE: Lysophosphatidic acid acyltransferase-beta (LPAAT-beta) is a transmembrane enzyme critical for the biosynthesis of phosphoglycerides whose product, phosphatidic acid, plays a key role in raf and AKT/mTor-mediated signal transduction. EXPERIMENTAL DESIGN: LPAAT-beta may be a novel target for anticancer therapy, and, thus, we examined the effects of a series of inhibitors of LPAAT-beta on multiple human non-Hodgkin's lymphoma cell lines in vitro and in vivo. RESULTS: We showed that five LPAAT-beta inhibitors at doses of 500 nmol/L routinely inhibited growth in a panel of human lymphoma cell lines in vitro by >90%, as measured by [3H]thymidine incorporation. Apoptotic effects of the LPAAT-beta inhibitors were evaluated either alone or in combination with the anti-CD20 antibody, Rituximab. The LPAAT-beta inhibitors induced caspase-mediated apoptosis at 50 to 100 nmol/L in up to 90% of non-Hodgkin's lymphoma cells. The combination of Rituximab and an LPAAT-beta inhibitor resulted in a 2-fold increase in apoptosis compared with either agent alone. To assess the combination of Rituximab and a LPAAT-beta inhibitor in vivo, groups of athymic mice bearing s.c. human Ramos lymphoma xenografts were treated with the LPAAT-beta inhibitor CT-32228 i.p. (75 mg/kg) daily for 5 d/wk x 4 weeks (total 20 doses), Rituximab i.p. (10 mg/kg) weekly x 4 weeks (4 doses total), or CT-32228 plus Rituximab combined. Treatment with either CT-32228 or Rituximab alone showed an approximate 50% xenograft growth delay; however, complete responses were only observed when the two agents were delivered together. CONCLUSIONS: These data suggest that Rituximab, combined with a LPAAT-beta inhibitor, may provide enhanced therapeutic effects through apoptotic mechanisms.