Understanding the actions of bisphosphonate drugs: inhibitory effects on macrophage populations outside the skeleton — ASN Events
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Understanding the actions of bisphosphonate drugs: inhibitory effects on macrophage populations outside the skeleton (#112)

Marcia A Munoz 1 , Julie Jurczyluk 1 , Niall Byrne 1 , Simon Junankar 1 , Hristo Zlatev 2 , Seppo Auriola 2 , Tri Phan 1 , Michael J Rogers 1
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. University of Eastern Finland, Kuopio, Finland

Bisphosphonates (BPs) are a class of calcium-seeking drugs used clinically to inhibit bone resorption. BPs such as zoledronic acid (ZOL) act by inhibiting FPP synthase, (an enzyme of the mevalonate pathway) in osteoclasts, causing accumulation of the upstream isoprenoid lipid IPP and simultaneously preventing the prenylation of small GTPase proteins required for bone resorption.

Various evidence suggests that BPs have pleiotropic effects outside the skeleton. In mice, we have shown that intravenous ZOL administration inhibits the prenylation of Rab GTPases in CD11b+ peritoneal macrophages. Using 2-photon intravital imaging of fluorescently-tagged BPs, we have also demonstrated that BPs diffuse from leaky vasculature and accumulate in 4T1 mammary tumour tissue by binding to microcalcifications. These drug-bound microcalcifications are then engulfed by tumour-associated macrophages (TAMs). To determine whether the intracellular concentration of ZOL achieved in TAMs in vivo is sufficient to affect the mevalonate pathway, we treated mice once-weekly for 4 weeks with intravenous "free" ZOL or an equivalent dose of liposome-encapsulated ZOL, which is efficiently phagocytosed by macrophages. Treatment of mice with free ZOL resulted in clear accumulation of IPP in TAMs, detected and quantified by LC-MS/MS analysis of immuno-purified TAMs. However, only liposomal ZOL had a clear inhibitory effect on Rab prenylation in TAMs, suggesting that free ZOL may not be released in large amounts after binding to tumour microcalcifications. In contrast, treatment of mice with just one dose of free ZOL did cause the accumulation of unprenylated Rab proteins in subcutaneous INA6 plasmacytoma tumours, indicating that some tumour types may be more susceptible to BP uptake than others.

Our data illustrate that ZOL can accumulate in TAMs in tumours outside the skeleton in concentrations that are sufficient to inhibit prenylation and/or cause IPP accumulation, particularly in some tumour types. How this affects TAM function in vivo remains to be determined.