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

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.

Randomized Clinical Trial of Zoledronic Acid in Multiple Myeloma Patients Undergoing High-Dose Chemotherapy and Stem-Cell Transplantation

“…• a decrease in the rate of sres 22-24 , which can be life-limiting events 25 ; and • indirect and direct anticancer effects 26 .…”

Accumulation of VEGFR2 in zoledronic acid-treated endothelial cells

“…1). BiS is a known inhibitor of farnesyl pyrophosphate synthase (16), and consequently prevents the biosynthesis of geranylgeranyl pyrophosphate (GGPP). We aimed to determine whether this pathway is involved in the attenuated endothelial response to VeGF.…”

“…1). Since BiS is a known inhibitor of farnesyl pyrophosphate synthase (16), by preventing the biosynthesis of GGPP we aimed to determine whether the addition of GGPP prevents the effect of Zol on huVec migration. We therefore also incubated endothelial cells with Zol and GGPP for 48 h, then allowed the huVecs to migrate towards VeGF.…”

Osteoclast activity modulates B-cell development in the bone marrow

“…In rodents, long-term treatment with ZA induces a mild osteopetrotic-like phenotype [25,26]. Regarding the B-cell lineage, ZA has an antitumor potential against myeloma plasma cells by inducing their apoptosis and interfering with the stromal cells necessary for their niche, but no data have been reported regarding ZA effect on B-cell precursors [27,28].…”