The HMG-CoA reductase inhibitor simvastatin overcomes cell adhesion-mediated drug resistance in multiple myeloma by geranylgeranylation of Rho protein and activation of Rho kinase.

Primary drug resistance is a major problem in multiple myeloma, an incurable disease of the bone marrow. Cell adhesion-mediated drug resistance (CAM-DR) causes strong primary resistance. By coculturing multiple myeloma cells with bone marrow stromal cells (BMSCs), we observed a CAM-DR of about 50% to melphalan, treosulfan, doxorubicin, dexamethasone, and bortezomib, which was not reversed by secreted soluble factors. Targeting the adhesion molecules lymphocyte function-associated antigen 1 (LFA-1) and very late antigen 4 (VLA-4) by monoclonal antibodies or by the LFA-1 inhibitor LFA703 reduced CAM-DR significantly. Only statins such as simvastatin and lovastatin, however, were able to completely restore chemosensitivity. All these effects were not mediated by deadhesion or reduced secretion of interleukin 6. Targeting geranylgeranyl transferase (GGTase) and Rho kinase by specific inhibitors (GGTI-298 and Y-27632), but not inhibition of farnesyl transferase (FTase) by FTI-277, showed similar reduction of CAM-DR. Addition of geranylgeranyl pyrophosphate (GG-PP), but not of farnesyl pyrophosphate (F-PP), was able to inhibit simvastatin-induced CAM-DR reversal. Our data suggest that the 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA)/GG-PP/Rho/Rho-kinase pathway mediates CAM-DR and that targeting this pathway may improve the efficacy of antimyeloma therapies by reduction of CAM-DR.

[1]  H. Thorlacius,et al.  Lymphocyte function antigen‐1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice , 2004, British journal of pharmacology.

[2]  M. Kamphuis,et al.  Protein geranylgeranylation is critical for the regulation of survival and proliferation of lymphoma tumor cells. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  C. Beam,et al.  Genotypic and phenotypic comparisons of de novo and acquired melphalan resistance in an isogenic multiple myeloma cell line model. , 2003, Cancer research.

[4]  M. Kamphuis,et al.  Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels. , 2003, Blood.

[5]  W. Dalton,et al.  Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death , 2003, Oncogene.

[6]  G. Meinhardt,et al.  Treosulfan is an effective inducer of cell death in myeloma cell lines and primary myeloma cells from patients , 2003, British journal of haematology.

[7]  Wen-Sen Lee,et al.  Lovastatin induces apoptosis of anaplastic thyroid cancer cells via inhibition of protein geranylgeranylation and de novo protein synthesis. , 2003, Endocrinology.

[8]  H. Thorlacius,et al.  A statin‐based inhibitor of lymphocyte function antigen‐1 protects against ischemia/reperfusion‐induced leukocyte adhesion in the colon , 2003, British journal of pharmacology.

[9]  Shu-mei Lai,et al.  Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells. , 2003, The Journal of clinical endocrinology and metabolism.

[10]  Bart Barlogie,et al.  A phase 2 study of bortezomib in relapsed, refractory myeloma. , 2003, The New England journal of medicine.

[11]  W. Dalton,et al.  Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms , 2003, Leukemia.

[12]  W. Dalton.  The tumor microenvironment: focus on myeloma. , 2003, Cancer treatment reviews.

[13]  J. Rubin,et al.  Wnt signaling in B-cell neoplasia , 2003, Oncogene.

[14]  B. Binder,et al.  Simvastatin Reduces the Expression of Adhesion Molecules in Circulating Monocytes From Hypercholesterolemic Patients , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[15]  C. Peschel,et al.  Influence of differing radiotherapy strategies on treatment results in diffuse large-cell lymphoma: a review. , 2003, Cancer treatment reviews.

[16]  S. Ralston,et al.  Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple myeloma , 2002, British journal of haematology.

[17]  S. Offermanns,et al.  Rho/Rho-kinase mediated signaling in physiology and pathophysiology , 2002, Journal of Molecular Medicine.

[18]  G. Meinhardt,et al.  Effect of novel modulators of protein kinase C activity upon chemotherapy-induced differentiation and apoptosis in myeloid leukemic cells , 2002, Anti-cancer drugs.

[19]  N. V. D. Donk,et al.  The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells , 2002, Leukemia.

[20]  G. Korczak-Kowalska,et al.  Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis‐dependent mechanism , 2002, International journal of cancer.

[21]  Xianwu Li,et al.  Inhibition of Protein Geranylgeranylation and RhoA/RhoA Kinase Pathway Induces Apoptosis in Human Endothelial Cells* , 2002, The Journal of Biological Chemistry.

[22]  C. Rao,et al.  Lamin B, caspase-3 activity, and apoptosis induction by a combination of HMG-CoA reductase inhibitor and COX-2 inhibitors: a novel approach in developing effective chemopreventive regimens. , 2002, International journal of oncology.

[23]  B. Halmos,et al.  Mechanism of lovastatin-induced apoptosis in intestinal epithelial cells. , 2002, Carcinogenesis.

[24]  H. Gerhartz,et al.  Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC–HOVON randomized phase III study (06914) , 2001, British journal of haematology.

[25]  P. Richardson,et al.  Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications , 2001, Leukemia.

[26]  P. Frenette.  Locking a leukocyte integrin with statins. , 2001, The New England journal of medicine.

[27]  Joerg Kallen,et al.  Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site , 2001, Nature Medicine.

[28]  P. Elliott,et al.  The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. , 2001, Cancer research.

[29]  M. Uguccioni.  [Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study]. , 2001, Italian heart journal. Supplement : official journal of the Italian Federation of Cardiology.

[30]  David Hunt,et al.  Effects of pravastatin in 3260 patients with unstable angina: results from the LIPID study , 2000, The Lancet.

[31]  U. Laufs,et al.  Targeting Rho in cardiovascular disease. , 2000, Circulation research.

[32]  T Matozaki,et al.  Small G-protein networks: their crosstalk and signal cascades. , 2000, Cellular signalling.

[33]  C. Myers,et al.  Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells. , 2000, Biochemical and biophysical research communications.

[34]  F. Bernini,et al.  New insights into the pharmacodynamic and pharmacokinetic properties of statins. , 1999, Pharmacology & therapeutics.

[35]  R. Kriwacki,et al.  Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. , 1999, Journal of molecular biology.

[36]  Y. Y. Lee,et al.  Lovastatin-induced inhibition of HL-60 cell proliferation via cell cycle arrest and apoptosis. , 1999, Anticancer research.

[37]  W. Dalton,et al.  Cell Adhesion Mediated Drug Resistance (CAM-DR): Role of Integrins and Resistance to Apoptosis in Human Myeloma Cell Lines , 1999 .

[38]  Shuh Narumiya,et al.  An essential part for Rho–associated kinase in the transcellular invasion of tumor cells , 1999, Nature Medicine.

[39]  F. Matsumura,et al.  Small GTP-binding Protein Rho Stimulates the Actomyosin System, Leading to Invasion of Tumor Cells* , 1998, The Journal of Biological Chemistry.

[40]  K. Kaibuchi,et al.  Formation of Actin Stress Fibers and Focal Adhesions Enhanced by Rho-Kinase , 1997, Science.

[41]  K. Keyomarsi,et al.  Lovastatin induction of cyclin-dependent kinase inhibitors in human breast cells occurs in a cell cycle-independent fashion. , 1997, Cancer research.

[42]  T. Libermann,et al.  Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. , 1996, Blood.

[43]  R. V. van Oers,et al.  Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures. , 1994, Blood.

[44]  C J Marshall,et al.  Protein prenylation: a mediator of protein-protein interactions. , 1993, Science.

[45]  Anne J. Ridley,et al.  The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors , 1992, Cell.

[46]  J. Goldstein,et al.  Regulation of the mevalonate pathway , 1990, Nature.

[47]  S. Rudikoff,et al.  Insulin-like growth factor I induces migration and invasion of human multiple myeloma cells. , 2004, Blood.

[48]  M. Oellerich,et al.  Treosulfan-induced apoptosis in acute myeloid leukemia cells is accompanied by translocation of protein kinase C delta and enhanced by bryostatin-1. , 2004, Experimental hematology.

[49]  L. Penn,et al.  Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. , 2002, Neoplasia.

[50]  J Otlewski,et al.  Structure of small G proteins and their regulators. , 2001, Acta biochimica Polonica.

[51]  玄田 拓哉.  Cell motility mediated by Rho and Rho-associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma , 2000 .

[52]  P. L. Bergsagel,et al.  Multiple myeloma: increasing evidence for a multistep transformation process. , 1998, Blood.

[53]  K. Kaibuchi,et al.  Small GTP-binding proteins. , 1992, International review of cytology.