Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma.

Abstract

In this study, we examined the effects of isoform-specific functional inhibitors of lysophosphatidic acid acyltransferase (LPAAT), which converts lysophosphatidic acid to phosphatidic acid, on multiple myeloma (MM) cell growth and survival. The LPAAT-beta inhibitors CT-32176, CT-32458, and CT-32615 induced >95% growth inhibition (P < 0.01) in MM.1S, U266, and RPMI8226 MM cell lines, as well as MM cells from patients (IC(50), 50-200 nM). We further characterized this LPAAT-beta inhibitory effect using CT-32615, the most potent inhibitor of MM cell growth. CT-32615 triggered apoptosis in MM cells via caspase-8, caspase-3, caspase-7, and poly (ADP-ribose) polymerase cleavage. Neither interleukin 6 nor insulin-like growth factor I inhibited CT-32615-induced apoptosis. Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors. CT-32615-induced apoptosis was associated with phosphorylation of p53 and c-Jun NH(2)-terminal kinase (JNK); conversely, JNK inhibitor SP600125 and dominant-negative JNK inhibited CT-32615-induced apoptosis. Importantly, CT-32615 inhibited tumor necrosis factor-alpha-triggered nuclear factor-kappaB activation but did not affect either tumor necrosis factor-alpha-induced p38 mitogen-activated protein kinase phosphorylation or interleukin 6-triggered signal transducers and activators of transcription 3 phosphorylation. Finally, although binding of MM cells to bone marrow stromal cells augments MM cell growth and protects against dexamethasone-induced apoptosis, CT-32615 induced apoptosis even of adherent MM cells. Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM.

• Authors: Teru Hideshima, Dharminder Chauhan, Toshiaki Hayashi, Klaus Podar, Masaharu Akiyama, Constantine Mitsiades, Nicholas MItsiades, Baoqing Gong, Lynn Bonham, Peter de Vries, Nikhil Munshi, Paul G Richardson, Jack W Singer, Kenneth C Anderson
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 23 Pg. 8428-36 (Dec 01 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14679006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Caspase Inhibitors
• Enzyme Inhibitors
• Interleukin-6
• Isoenzymes
• NF-kappa B
• Tumor Necrosis Factor-alpha
• Tumor Suppressor Protein p53
• Thalidomide
• Insulin-Like Growth Factor I
• Dexamethasone
• Acyltransferases
• 2-acylglycerophosphate acyltransferase
• Poly(ADP-ribose) Polymerases
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases
• CASP3 protein, human
• CASP7 protein, human
• Caspase 3
• Caspase 7
• Caspases

Topics

• Acyltransferases (antagonists & inhibitors)
• Antineoplastic Agents (pharmacology)
• Caspase 3
• Caspase 7
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Line, Tumor
• Dexamethasone (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Humans
• Insulin-Like Growth Factor I (antagonists & inhibitors, pharmacology)
• Interleukin-6 (antagonists & inhibitors, pharmacology)
• Isoenzymes (antagonists & inhibitors)
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Multiple Myeloma (drug therapy, enzymology)
• NF-kappa B (metabolism)
• Phosphorylation (drug effects)
• Poly(ADP-ribose) Polymerases (metabolism)
• Thalidomide (analogs & derivatives, pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Tumor Suppressor Protein p53 (metabolism)