Effects of an HMG-CoA reductase inhibitor, simvastatin, on human myeloma cells.
To look for new candidates for agents to use in maintenance therapy for myeloma patients, the growth inhibitory effects of a 3-hydroxy-3-mehtylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin), simvastatin, was analyzed using human myeloma cell lines. Several investigations have indicated growth reduction in certain lineages of cancer cells including one report on myeloma, and inhibitory effects of statins on GTPases and involving MAP-kinases. Most (12 out of 13) myeloma lines examined showed growth inhibition when cultured with various concentrations (1-30 microM) of simvastatin in a dose-dependent manner. Simvastatin in combination with other biological response modifiers such as ATRA or DEX had additional effects on growth. In addition, anti-oxides prevented the simvastatin-induced growth inhibition and apoptosis. Furthermore, myeloma cells treated with simvastatin clearly showed inactivation of various MAP-kinase pathways such as ERK1/2, MEK1/2, JNK, and p38. Based on these findings, statins may be suitable for clinical usage in maintenance therapy for myeloma patients.
Otsuki
Takemi
T
Department of Hygiene, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan. takemi@med.kawasaki-m.ac.jp
Sakaguchi
Haruko
H
Hatayama
Tamayo
T
Fujii
Tomohiro
T
Tsujioka
Takayuki
T
Sugihara
Takashi
T
Takata
Akiko
A
Hyodoh
Fuminori
F
Eto
Masaaki
M
D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000819:agonists / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016898:Interferon-alpha / Q000819:agonists / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D014212:Tretinoin / Q000819:agonists / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000975:Antioxidants; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016898:Interferon-alpha; D014212:Tretinoin; D003907:Dexamethasone; D019821:Simvastatin; C482128:MAP2K2 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048670:MAP Kinase Kinase 4; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases