Zoledronic acid-induced IPP/ApppI production in vivo

Mönkkönen, Hannu; Ottewell, Penelope D.; Kuokkanen, Johanna; Mönkkönen, Jukka; Auriola, Seppo; Holen, Ingunn

doi:10.1016/j.lfs.2007.08.007

Cited by 61 publications

(47 citation statements)

References 16 publications

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“…Moreover, triphosphoric acid 1-adenosin-59-yl ester 3-(3-methylbut-3-enyl) ester (ApppI), an adenylated derivative of IPP, accumulates in cells overproducing IPP (11,12). We found that it is naturally produced in the Vg9Vd2 tumoral target Daudi as well.…”

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confidence: 90%

F1-Adenosine Triphosphatase Displays Properties Characteristic of an Antigen Presentation Molecule for Vγ9Vδ2 T Cells

Mookerjee‐Basu

Vantourout

Martinez

et al. 2010

The Journal of Immunology

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confidence: 90%

F1-Adenosine Triphosphatase Displays Properties Characteristic of an Antigen Presentation Molecule for Vγ9Vδ2 T Cells

Mookerjee‐Basu

Vantourout

Martinez

et al. 2010

The Journal of Immunology

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“…The quantitative analysis of IPP/ApppI, and AppCCl 2 p in cell extracts was performed as previously described [21] by using a HPLC electrospray ionization mass A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 11…”

Section: Mass Spectrometry Analysismentioning

confidence: 99%

“…Disruption of the lipid modification of these proteins induces a series of changes leading to altered cell activity and indirect apoptosis, and has been suggested to underlie the cytotoxic effects of N-BPs. 6 However, in addition to the loss of prenylated proteins, inhibition of FPPS by NBPs in the MVP causes intracellular accumulation of isopentenyl pyrophosphate (IPP) and consequently induces the biosynthesis of a novel pro-apoptotic ATP analog ApppI (triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) ester), in vitro [17][18][19][20] and in vivo [19,21]. Recently we observed that in addition to IPP/ApppI formation, NBPs induce isomeric dimethylallyl pyrophosphate (DMAPP) accumulation and consequent ApppD (triphosphoric acid 1-adenosin-5'-yl ester 3-(3-methylbut-2-enyl) ester) production [22].…”

Section: Introductionmentioning

confidence: 99%

Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells

Räikkönen

Mönkkönen

Auriola

et al. 2010

Biochemical Pharmacology

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To cite this version:Johanna Räikkönen, Hannu Mönkkönen, Seppo Auriola, Jukka Mönkkönen. Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells. Biochemical Pharmacology, Elsevier, 2009, 79 (5) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 35A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 This study represents a novel insight into the mechanism of action of MVP intermediates on the regulation of MVP after FPPS inhibition. The data implies that in addition to the previously reported effects on rescuing protein prenylation, MVP intermediates can preserve cell activity by inhibiting the accumulation of IPP/ApppI via

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“…Cell stress and transformation increase Mev activity and accelerate the formation of intracellular phosphorylated metabolites, whose accumulation in excess of physiological levels is detected by gd T cells and renders the immune system able to sense potential threats such as stressed or transformed cells (6). IPP levels are increased by drugs such as aminobisphosphonates (NBP) that selectively target farnesyl-pyrophosphate synthase (FPPS) in the Mev pathway (6)(7)(8). When NBP are used to target the Mev pathway of professional APC, such as monocytes (MC) and dendritic cells (DC), a quick and robust proliferative expansion of gd T cells with antitumor activity is induced (9)(10)(11).…”

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Immune Modulation by Zoledronic Acid in Human Myeloma: An Advantageous Cross-Talk between Vγ9Vδ2 T Cells, αβ CD8+ T Cells, Regulatory T Cells, and Dendritic Cells

Castella¹,

Riganti

Fiore

et al. 2011

The Journal of Immunology

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Vγ9Vδ2 T cells play a major role as effector cells of innate immune responses against microbes, stressed cells, and tumor cells. They constitute <5% of PBLs but can be expanded by zoledronic acid (ZA)-treated monocytes or dendritic cells (DC). Much less is known about their ability to act as cellular adjuvants bridging innate and adaptive immunity, especially in patients with cancer. We have addressed this issue in multiple myeloma (MM), a prototypic disease with several immune dysfunctions that also affect γδ T cells and DC. ZA-treated MM DC were highly effective in activating autologous γδ T cells, even in patients refractory to stimulation with ZA-treated monocytes. ZA inhibited the mevalonate pathway of MM DC and induced the intracellular accumulation and release into the supernatant of isopentenyl pyrophosphate, a selective γδ T cell activator, in sufficient amounts to induce the proliferation of γδ T cells. Immune responses against the tumor-associated Ag survivin (SRV) by MHC-restricted, SRV-specific CD8+ αβ T cells were amplified by the concurrent activation of γδ T cells driven by autologous DC copulsed with ZA and SRV-derived peptides. Ancillary to the isopentenyl pyrophosphate-induced γδ T cell proliferation was the mevalonate-independent ZA ability to directly antagonize regulatory T cells and downregulate PD-L2 expression on the DC cell surface. In conclusion, ZA has multiple immune modulatory activities that allow MM DC to effectively handle the concurrent activation of γδ T cells and MHC-restricted CD8+ αβ antitumor effector T cells.

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Zoledronic acid-induced IPP/ApppI production in vivo

Cited by 61 publications

References 16 publications

F1-Adenosine Triphosphatase Displays Properties Characteristic of an Antigen Presentation Molecule for Vγ9Vδ2 T Cells

F1-Adenosine Triphosphatase Displays Properties Characteristic of an Antigen Presentation Molecule for Vγ9Vδ2 T Cells

Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells

Immune Modulation by Zoledronic Acid in Human Myeloma: An Advantageous Cross-Talk between Vγ9Vδ2 T Cells, αβ CD8+ T Cells, Regulatory T Cells, and Dendritic Cells

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