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Cancer Therapy: Preclinical

Induction of Apoptosis Using Inhibitors of Lysophosphatidic Acid Acyltransferase-β and Anti-CD20 Monoclonal Antibodies for Treatment of Human Non-Hodgkin's Lymphomas

John M. Pagel, Christian Laugen, Lynn Bonham, Robert C. Hackman, David M. Hockenbery, Rama Bhatt, David Hollenback, Heather Carew, Jack W. Singer and Oliver W. Press
John M. Pagel
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Christian Laugen
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Lynn Bonham
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Robert C. Hackman
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David M. Hockenbery
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Rama Bhatt
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David Hollenback
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Heather Carew
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Jack W. Singer
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Oliver W. Press
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DOI: 10.1158/1078-0432.CCR-04-2352 Published July 2005
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Abstract

Purpose: Lysophosphatidic acid acyltransferase-β (LPAAT-β) 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-β may be a novel target for anticancer therapy, and, thus, we examined the effects of a series of inhibitors of LPAAT-β on multiple human non–Hodgkin's lymphoma cell lines in vitro and in vivo.

Results: We showed that five LPAAT-β 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-β inhibitors were evaluated either alone or in combination with the anti-CD20 antibody, Rituximab. The LPAAT-β 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-β inhibitor resulted in a 2-fold increase in apoptosis compared with either agent alone. To assess the combination of Rituximab and a LPAAT-β inhibitor in vivo, groups of athymic mice bearing s.c. human Ramos lymphoma xenografts were treated with the LPAAT-β inhibitor CT-32228 i.p. (75 mg/kg) daily for 5 d/wk × 4 weeks (total 20 doses), Rituximab i.p. (10 mg/kg) weekly × 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-β inhibitor, may provide enhanced therapeutic effects through apoptotic mechanisms.

  • Non-Hodgkin's Lymphoma
  • Lysophosphatidic acid acyltransferase
  • CD20
  • Rituximab
  • Apoptosis
  • Caspase

Footnotes

  • ↵6 J. Singer, personal communication.

  • Grant support: Lymphoma Research Foundation Career Development Award (JMP), American Society of Clinical Oncology Young Investigator Award (JMP), NIH grant K12 CA76930 (JMP), Hext Foundation, and Penny E. Petersen Memorial Fund.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted April 19, 2005.
    • Received November 16, 2004.
    • Revision received March 31, 2005.
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Clinical Cancer Research: 11 (13)
July 2005
Volume 11, Issue 13
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Induction of Apoptosis Using Inhibitors of Lysophosphatidic Acid Acyltransferase-β and Anti-CD20 Monoclonal Antibodies for Treatment of Human Non-Hodgkin's Lymphomas
John M. Pagel, Christian Laugen, Lynn Bonham, Robert C. Hackman, David M. Hockenbery, Rama Bhatt, David Hollenback, Heather Carew, Jack W. Singer and Oliver W. Press
Clin Cancer Res July 1 2005 (11) (13) 4857-4866; DOI: 10.1158/1078-0432.CCR-04-2352

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Induction of Apoptosis Using Inhibitors of Lysophosphatidic Acid Acyltransferase-β and Anti-CD20 Monoclonal Antibodies for Treatment of Human Non-Hodgkin's Lymphomas
John M. Pagel, Christian Laugen, Lynn Bonham, Robert C. Hackman, David M. Hockenbery, Rama Bhatt, David Hollenback, Heather Carew, Jack W. Singer and Oliver W. Press
Clin Cancer Res July 1 2005 (11) (13) 4857-4866; DOI: 10.1158/1078-0432.CCR-04-2352
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