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

Abstract

Purpose: Lysophosphatidic acid acyltransferase-h (LPAAT-h) 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-h may be a novel target for anticancer therapy, and, thus, we examined the effects of a series of inhibitors of LPAAT-h on multiple human non^Hodgkin's lymphoma cell lines in vitro and in vivo. 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-h inhibitor, may provide enhanced therapeutic effects through apoptotic mechanisms.

Glycerolipid Metabolism and Signaling in Health and Disease

“…Such lipodystrophy due to either inherited or acquired inactivating mutations of AGPAT-2 is associated with diabetes (75), possibly due to the ectopic accumulation of fat in nonadipose tissues, thus causing insulin resistance and perhaps ␤-cell dysfunction as well (76,77). Like many other lipid synthesis enzymes, AGPAT-2 is overexpressed in various cancers (78), and specific inhibition of AGPAT induces apoptosis of cancer cells (79,80). PA can also be synthesized from DAG by DAG kinase (DAGK), although this reaction may be more important in the generation of lipid-signaling molecules than for TG synthesis (81).…”

Chemical modulation of glycerolipid signaling and metabolic pathways

“…The most potent triazine found in this study was CT-32228 (Fig. 8C), which had an IC 50 of 0.06 μM whereas CT-32521, the most potent pyrimidine-based inhibitor displays an IC 50 of 0.16 μM [314]. Compound CT-32228 inhibits proliferation of several non-Hodgkins lymphoma cell lines in vitro with IC 50 values between 0.025 to 0.05 μM.…”

“…Compound CT-32228 inhibits proliferation of several non-Hodgkins lymphoma cell lines in vitro with IC 50 values between 0.025 to 0.05 μM. However, relevant doses of CT-32228 in vivo resulted in off-target toxicity, making the compound unsuitable for clinical development [314]. …”

Direct Effect of Rituximab in B-Cell–Derived Lymphoid Neoplasias: Mechanism, Regulation, and Perspectives

“…In an in vivo model, concurrent administration of 4HPR and rituximab prevented disease progression in a minimal disease model and induced complete response in 80% of animals with established tumors (54). Similarly, combining lysophosphatidic acid acyltransferase-b inhibitors with rituximab in NHL cell lines resulted in a 2-fold increase in apoptosis compared with either agent alone and induced complete response in athymic mice bearing subcutaneous human Ramos lymphoma xenografts (55). Inhibition of survivin, a protein involved in inhibition of apoptosis and cell-cycle regulation, using antisense oligonucleotides in combination with rituximab has been shown to decrease the viability of DoHH2 cells in culture compared with either agent alone.…”