Zoledronate has an antitumor effect and induces actin rearrangement in dexamethasone-resistant myeloma cells.
New strategies are needed to overcome the resistance of multiple myeloma (MM) to dexamethasone (Dex). Several recent in vitro studies demonstrated the antitumor effect of nitrogen-containing amino-bisphosphonates (N-BPs) in various tumor cell lines. Inhibition of the prenylation of small G proteins is assumed to be one of the principal mechanisms by which N-BPs exert their effects. There have been few reports on N-BP treatment of MM cells that are resistant to Dex. Additionally, it is not known how small G proteins are altered in N-BP-treated MM cells. In this study, we evaluated the effect of the most potent N-BP, zoledronate (ZOL), on a Dex-resistant human MM cell subline (Dex-R) that we established from the well-documented RPMI8226 cell line. ZOL reduced the viability and induced apoptosis of Dex-R cells. Some of the ZOL-treated RPMI8226 cells and ZOL-treated Dex-R cells were elongated; however, elongated cells were not seen among the Dex-treated RPMI8226 cells. Furthermore, we found that portions of the small G proteins, Rho and Rap1A, were unprenylated in the ZOL-treated MM cells. Geranylgeraniol reduced the above-mentioned ZOL-induced effects. These findings suggest that ZOL may be beneficial for the treatment of Dex-resistant MM by suppressing the processing of RhoA and Rap1A.
Koizumi
Masayuki
M
Division of Hematology, Department of Clinical Cell Biology, Chiba University Graduate School of Medicine, Inohana, Chuo-ku, Chiba City, Chiba, Japan.
Nakaseko
Chiaki
C
Ohwada
Chikako
C
Takeuchi
Masahiro
M
Ozawa
Shinichi
S
Shimizu
Naomi
N
Cho
Ryuko
R
Nishimura
Miki
M
Saito
Yasushi
Y
D000199:Actins / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004164:Diphosphonates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004224:Diterpenes / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017368:Protein Prenylation / Q000187:drug effects; D000077211:Zoledronic Acid; D020827:rap1 GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000187:drug effects / Q000378:metabolism
D000199:Actins; D000970:Antineoplastic Agents; D004164:Diphosphonates; D004224:Diterpenes; D007093:Imidazoles; C430803:RAP1A protein, human; C066737:RHOA protein, human; D000077211:Zoledronic Acid; D003907:Dexamethasone; C017338:geranylgeraniol; D020827:rap1 GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein