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The bisphosphonate zoledronic acid has antimyeloma activity in vivo by inhibition of protein prenylation
Author(s) -
Guenther Andreas,
Gordon Sharon,
Tiemann Markus,
Burger Renate,
Bakker Frank,
Green Jonathan R.,
Baum Wolfgang,
Roelofs Anke J.,
Rogers Michael J.,
Gramatzki Martin
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24758
Subject(s) - bisphosphonate , prenylation , zoledronic acid , in vivo , farnesyl pyrophosphate , cancer research , bone resorption , mevalonate pathway , multiple myeloma , western blot , farnesyl diphosphate synthase , apoptosis , chemistry , pharmacology , medicine , enzyme , biology , biochemistry , atp synthase , biosynthesis , osteoporosis , microbiology and biotechnology , gene
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.