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


METHODS
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.
Pagel
John M
JM
Fred Hutchinson Cancer Research Center; Department of Medicine, University of Washington, Seattle, Washington 98109, USA. jpagel@fhcrc.org
Laugen
Christian
C
Bonham
Lynn
L
Hackman
Robert C
RC
Hockenbery
David M
DM
Bhatt
Rama
R
Hollenback
David
D
Carew
Heather
H
Singer
Jack W
JW
Press
Oliver W
OW
D000217:Acyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D000069283:Rituximab; D013047:Specific Pathogen-Free Organisms; D016019:Survival Analysis; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*; D014316:Tritium; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; C505793:CT-32228; D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; D014227:Triazines; D014316:Tritium; D000069283:Rituximab; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020169:Caspases; D013936:Thymidine