The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation

Andreas Guenther, Sharon Gordon, Markus Tiemann, Renate Burger, Frank Bakker, Jonathan R Green, Wolfgang Baum, Anke J Roelofs, Michael J Rogers, Martin Gramatzki

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99 Citations (Scopus)

Abstract

Nitrogen-containing bisphosphonates (N-BPs) are effective antiosteolytic agents in patients with multiple myeloma. Preclinical studies have also demonstrated that these agents have direct antitumor effects in vitro and can reduce tumor burden in a variety of animal models, although it is not clear whether such effects are caused by direct actions on tumor cells or by inhibition of bone resorption. N-BPs prevent bone destruction in myeloma by inhibiting the enzyme farnesyl pyrophosphate synthase in osteoclasts, thereby preventing the prenylation of small GTPase signaling proteins. In this study, utilizing a plasmacytoma xenograft model without complicating skeletal lesions, treatment with zoledronic acid (ZOL) led to significant prolongation of survival in severe combined immunodeficiency mice inoculated with human INA-6 plasma cells. Following treatment with a clinically relevant dose of ZOL, histological analysis of INA-6 tumors from the peritoneal cavity revealed extensive areas of apoptosis associated with poly (ADP-ribose) polymerase cleavage. Furthermore, Western blot analysis of tumor homogenates demonstrated the accumulation of unprenylated Rap1A, indicative of the uptake of ZOL by nonskeletal tumors and inhibition of farnesyl pyrophosphate synthase. These studies provide, for the first time, clear evidence that N-BPs have direct antitumor effects in plasma cell tumors in vivo and this is executed by a molecular mechanism similar to that observed in osteoclasts.
Original languageEnglish
Pages (from-to)239-246
Number of pages8
JournalInternational Journal of Cancer
Volume126
Issue number1
Early online date20 Jul 2009
DOIs
Publication statusPublished - 1 Jan 2010

Keywords

  • animals
  • apoptosis
  • bonedensity conservation agents
  • cell line, tumor
  • cell proliferation
  • diphosphonates
  • disease models, animal
  • female
  • humans
  • imidazoles
  • mice
  • mice, SCID
  • multiple myeloma
  • protein prenylation
  • transplantation, heterologous
  • N-bisphosphonates
  • prenylation inhibitor
  • multiple myeloma
  • animal model

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    Guenther, A., Gordon, S., Tiemann, M., Burger, R., Bakker, F., Green, J. R., Baum, W., Roelofs, A. J., Rogers, M. J., & Gramatzki, M. (2010). The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation. International Journal of Cancer, 126(1), 239-246. https://doi.org/10.1002/ijc.24758