A novel ginseng saponin metabolite induces apoptosis and down-regulates fibroblast growth factor receptor 3 in myeloma cells.

Ginseng (the root of Panax ginseng C.A. Meyer, Araliaceae) has been used as a crude drug taken orally for preventive and therapeutic purposes in Asian countries as a traditional medicine. In the current study, we have investigated the antitumor effect of a novel ginseng protopanaxadiol saponin bacterial metabolic derivative, 20-O-beta-D-glucopyranosyl-20(S)-protopanaxadiol (IH-901), in eight human myeloma cell lines. IH-901 inhibited the proliferation of all myeloma cell lines examined. Despite the fibroblast growth factor receptor 3 (FGFR3) overexpression due to a chromosomal translocation t(4;14)(q16.3;q32.3) in KMS-11 myeloma cells, IH-901 induced apoptosis in a dose- and time-dependent way in this cell line. Treatment of KMS-11 with IH-901 resulted in the formation of internucleosomal DNA fragments, poly (ADP-ribose) polymerase cleavage, and the activation of caspase-3. IH-901 also caused the down-regulation of FGFR3 mRNA and protein expression and inhibited ERK activity in KMS-11 cells. Our results demonstrate that IH-901 induces apoptosis and inhibits FGFR3 expression and signaling in KMS-11 cells, suggesting candidacy for the chemoprevention and the treatment of myeloma.

[1]  Y. Bang,et al.  Attenuation of transforming growth factor beta-induced growth inhibition in human hepatocellular carcinoma cell lines by cyclin D1 overexpression. , 2002, Biochemical and biophysical research communications.

[2]  A. Neri,et al.  Deregulated FGFR3 mutants in multiple myeloma cell lines with t(4;14): comparative analysis of Y373C, K650E and the novel G384D mutations , 2001, Oncogene.

[3]  A. Neri,et al.  Characterization of the t(4;14)(p16.3;q32) in the KMS-18 multiple myeloma cell line , 2001, Leukemia.

[4]  W. Kuehl,et al.  Activated fibroblast growth factor receptor 3 is an oncogene that contributes to tumor progression in multiple myeloma. , 2001, Blood.

[5]  J. Sung,et al.  Induction of apoptosis by a novel intestinal metabolite of ginseng saponin via cytochrome c-mediated activation of caspase-3 protease. , 2000, Biochemical pharmacology.

[6]  P. L. Bergsagel,et al.  Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis. , 2000, Blood.

[7]  D. Mercola,et al.  Inhibition of Extracellular Signal-regulated Protein Kinase or c-Jun N-terminal Protein Kinase Cascade, Differentially Activated by Cisplatin, Sensitizes Human Ovarian Cancer Cell Line* , 1999, The Journal of Biological Chemistry.

[8]  D. Chopin,et al.  Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas , 1999, Nature Genetics.

[9]  E. Yazlovitskaya,et al.  Cisplatin-induced activation of mitogen-activated protein kinases in ovarian carcinoma cells: inhibition of extracellular signal-regulated kinase activity increases sensitivity to cisplatin. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  J. Sung,et al.  In vitro antigenotoxic activity of novel ginseng saponin metabolites formed by intestinal bacteria. , 1998, Planta medica.

[11]  N. Holbrook,et al.  The cellular response to oxidative stress: influences of mitogen-activated protein kinase signalling pathways on cell survival. , 1998, The Biochemical journal.

[12]  J. Sung,et al.  Ginseng intestinal bacterial metabolite IH901 as a new anti-metastatic agent , 1997, Archives of pharmacal research.

[13]  M. Rocchi,et al.  A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. , 1997, Blood.

[14]  Y. Benno,et al.  Role of Human Intestinal Prevotella oris in Hydrolyzing Ginseng Saponins , 1997, Planta medica.

[15]  O. Linderkamp,et al.  Fas- or Ceramide-induced Apoptosis Is Mediated by a Rac1-regulated Activation of Jun N-terminal Kinase/p38 Kinases and GADD153* , 1997, The Journal of Biological Chemistry.

[16]  E. Schröck,et al.  Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3 , 1997, Nature Genetics.

[17]  Yuri Lazebnik,et al.  Multiple species of CPP32 and Mch2 are the major active caspases present in apoptotic cells , 1997, The EMBO journal.

[18]  D. Donoghue,et al.  FGFR activation in skeletal disorders: too much of a good thing. , 1997, Trends in genetics : TIG.

[19]  M. Göke,et al.  Signal Transduction Pathway of Human Fibroblast Growth Factor Receptor 3 , 1997, The Journal of Biological Chemistry.

[20]  R. Davis,et al.  The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. , 1996, The Journal of biological chemistry.

[21]  E. Krebs,et al.  Involvement of stress-activated protein kinase and p38 mitogen-activated protein kinase in mIgM-induced apoptosis of human B lymphocytes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Sung,et al.  Main ginseng saponin metabolites formed by intestinal bacteria. , 1996, Planta medica.

[23]  D. Donoghue,et al.  Profound ligand-independent kinase activation of fibroblast growth factor receptor 3 by the activation loop mutation responsible for a lethal skeletal dysplasia, thanatophoric dysplasia type II , 1996, Molecular and cellular biology.

[24]  D. Ornitz,et al.  Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia , 1996, Nature Genetics.

[25]  G. Gores,et al.  The role of proteases during apoptosis , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  Qingbo Xu,et al.  Activation of Mitogen-activated Protein Kinase by HO , 1996, The Journal of Biological Chemistry.

[27]  Michael E. Greenberg,et al.  Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis , 1995, Science.

[28]  J. Schlessinger,et al.  Reduced Activation of RAF-1 and MAP Kinase by a Fibroblast Growth Factor Receptor Mutant Deficient in Stimulation of Phosphatidylinositol Hydrolysis (*) , 1995, The Journal of Biological Chemistry.

[29]  M. Jaye,et al.  Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation , 1994, Cell.

[30]  R. Kasai,et al.  Inhibitory effect of some triterpenoid saponins on glucose transport in tumor cells and its application to in vitro cytotoxic and antiviral activities. , 1994, Planta medica.

[31]  D. Johnson,et al.  Structural and functional diversity in the FGF receptor multigene family. , 1993, Advances in cancer research.

[32]  T. Morgan,et al.  Bromodeoxyuridine incorporation into DNA of human leukemia cells is not concentration dependent. , 1990, Cytometry.

[33]  S. Cole,et al.  Use of the MTT assay for rapid determination of chemosensitivity of human leukemic blast cells. , 1988, Leukemia research.