title: A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates.
abstract: 1. Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of diseases with excess bone resorption. On the basis of their molecular mechanism of action, bisphosphonates can be divided into two pharmacological classes; nitrogen-containing (N-BPs) and non-nitrogen-containing bisphosphonates (non-N-BP). Both classes induce apoptosis but they evoke it differently; N-BPs by inhibiting the intracellular mevalonate pathway and protein isoprenylation, and non-N-BPs via cytotoxic ATP analog-type metabolites. N-BPs are not metabolized to ATP analogs, but we report here that these bisphosphonates can induce formation of a novel ATP analog (ApppI) as a consequence of the inhibition of the mevalonate pathway in cells. We also investigated whether ApppI is involved in the apoptosis induced by N-BPs. 2. Mass spectrometry and NMR were used to identify ApppI in N-BP treated osteoclasts, macrophages and glioma cells. The potency of different bisphosphonates to promote ApppI production was tested in J774 macrophages. The effects of ApppI on ADP/ATP translocase in isolated mitochondria and its capability to induce apoptosis in osteoclasts were also studied. 3. ApppI production correlated well with the capacity of N-BPs to inhibit mevalonate pathway. ApppI inhibited the mitochondrial ADP/ATP translocase and caused apoptosis in osteoclasts. 4. In conclusion, these findings provide the basis for a new mechanism of action for N-BPs. Some of these very potent bisphosphonates, such as zoledronic acid, represent a third class of bisphosphonates that can act both via the inhibition of the mevalonate pathway and by the blockade of mitochondrial ADP/ATP translocase, which is known to be involved in the induction of apoptosis.
authors.affiliation: Department of Pharmaceutics, University of Kuopio, POB 1627, Kuopio, FIN-70211, Finland. hannu.monkkonen@uku.fi
authors.forename: Hannu
authors.initials: H
authors.lastname: Mönkkönen
authors.forename: Seppo
authors.initials: S
authors.lastname: Auriola
authors.forename: Petri
authors.initials: P
authors.lastname: Lehenkari
authors.forename: Maarit
authors.initials: M
authors.lastname: Kellinsalmi
authors.forename: Ilmo E
authors.initials: IE
authors.lastname: Hassinen
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: Jukka
authors.initials: J
authors.lastname: Mönkkönen
mesh_terms: D033741:Adenine Nucleotide Translocator 1 / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D019906:Nuclear Magnetic Resonance, Biomolecular; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D033741:Adenine Nucleotide Translocator 1; D004164:Diphosphonates; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate