Zoledronate has an antitumor effect and induces actin rearrangement in dexamethasone-resistant myeloma cells

• Published in: European journal of haematology Vol. 79; no. 5; pp. 382 - 391
• Main Authors: Koizumi, Masayuki, Nakaseko, Chiaki, Ohwada, Chikako, Takeuchi, Masahiro, Ozawa, Shinichi, Shimizu, Naomi, Cho, Ryuko, Nishimura, Miki, Saito, Yasushi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2007
• Subjects: Actins - drug effects; Antineoplastic Agents - antagonists & inhibitors; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; bisphosphonate; Blotting, Western; Cell Line, Tumor; Cell Survival - drug effects; dexamethasone; Dexamethasone - pharmacology; Diphosphonates - antagonists & inhibitors; Diphosphonates - pharmacology; Diterpenes - pharmacology; Drug Resistance, Neoplasm; Humans; Imidazoles - antagonists & inhibitors; Imidazoles - pharmacology; multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Protein Prenylation - drug effects; rap1 GTP-Binding Proteins - drug effects; rap1 GTP-Binding Proteins - metabolism; Rap1A; RhoA; rhoA GTP-Binding Protein - drug effects; rhoA GTP-Binding Protein - metabolism; zoledronate
• ISSN: 0902-4441; 1600-0609
• DOI: 10.1111/j.1600-0609.2007.00957.x

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.