Bisphosphonates Are Incorporated into Adenine Nucleotides by Human Aminoacyl-tRNA Synthetase Enzymes

Rogers, Michael J.; Brown, Richard J.; Hodkin, V; Blackburn, G. Michael; Russell, R. G. G.; Watts, Donald J.

doi:10.1006/bbrc.1996.1113

Cited by 105 publications

(60 citation statements)

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“…(45) In 2003, the discovery in GACI that the cell-surface PPigenerating enzyme, ENPP1, has diminished activity from loss-offunction mutations in its gene (6) provided rationale for ''replenishment'' of PPi effects using BPs. Nevertheless, concerns for EHDP treatment included: (i) expectation that it would not ameliorate any vascular fibroblast proliferation, (4) which could be irreversible, (46) and (ii) BPs incorporate into non-hydrolyzable adenosine-containing compounds, (47,48) which are toxic to cells. (49,50) Thus, BP excesses in non-osseous tissues could have unpredictable and undesirable effects.…”

Section: Discussionmentioning

confidence: 99%

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

Otero

Gottesman

McAlister

et al. 2012

Journal of Bone and Mineral Research

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Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of GACI patients die by 6 months of age from cardiac ischemia and congestive heart failure. The first-generation bisphosphonate etidronate (EHDP; ethane-1-hydroxy-1,1-diphosphonic acid, also known as 1-hydroxyethylidene-bisphosphonate) inhibits bone resorption and can mimic endogenous inorganic pyrophosphate by blocking mineralization. With EHDP therapy for GACI, AC may resolve without recurrence upon treatment cessation. Skeletal disease is not an early characteristic of GACI, but rickets can appear from acquired hypophosphatemia or prolonged EHDP therapy. We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC was gone after 5 months of EHDP therapy during infancy, but GACI-related joint calcifications progressed. He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal. Serum osteocalcin was low and the brain isoform of creatine kinase and tartrate-resistant acid phosphatase 5b (TRAP-5b) were elevated as in osteopetrosis. Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, long-bone bowing, widened physes, as well as metaphyseal osteosclerosis, cupping and fraying, and ''tongues'' of radiolucency. Radiographic features of osteopetrosis included osteosclerosis and femoral Erlenmeyer flask deformity. After stopping EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in GACI from protracted EHDP therapy. Although EHDP treatment is lifesaving in GACI, surveillance for toxicity is crucial. ß

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Section: Discussionmentioning

confidence: 99%

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

Otero

Gottesman

McAlister

et al. 2012

Journal of Bone and Mineral Research

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“…The ratio of IPP and DMAPP in all cell extracts was approximately 1:4. The same treatment protocol was tested, except that ZOL was replaced with non-N-BP clodronate (500 µM), to clarify the functionality of the aminoacyl-tRNA-synthase enzyme, known to catalyze ATP-analogs from non-N-BPS [23], and which is proposed to catalyze also the formation of ApppI from IPP. The cells were observed to metabolize clodronate into AppCCl 2 p regardless of isoprenoid treatments, and therefore the functionality of the aminoacyl-tRNA-synthase was not affected (Fig.…”

Section: Page 14 Of 35mentioning

confidence: 99%

“…Formation of ApppI from IPP is most probably catalyzed by the same metabolic pathway (i.e. aminoacyltRNA-synthetases) [23] as the nonhydrolyzable AppCp-type ATP analogs of nonnitrogen containing bisphosphonates (non-N-BPs), such as clodronate [18]. Similar to AppCCl 2 p (i.e., a metabolite of clodronate) [24], ApppI interferes with mitochondrial function and induces apoptosis in osteoclasts [17].…”

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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“…Clodronate induces apoptosis of osteoclasts not via inhibition of the MVA pathway, but by forming toxic analogues of ATP. 44 We investigated whether this different type of bisphosphonate could also induce synergistic induction of apoptosis when used in sequence with doxorubicin. We treated MCF7 cells with doxorubicin, as per drug sequence 1, followed this time by clodronate for 24 hr, followed by a drug-free incubation period of 48 hr, prior to counting of apoptotic cells.…”

Section: Clodronate and Doxorubicin Do Not Induce Increased Apoptosismentioning

confidence: 99%

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

Neville-Webbe

Rostami‐Hodjegan

Evans

et al. 2004

Intl Journal of Cancer

146

104

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We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence-and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.Key words: breast cancer; apoptosis; zoledronic acid; doxorubicin; synergistic interaction Zoledronic acid is a potent third-generation nitrogen-containing bisphosphonate and is the only bisphosphonate licensed to treat bone metastases from a variety of solid tumors and in multiple myeloma. In clinical practice, an increasing number of breast and prostate cancer patients are receiving zoledronic acid at earlier stages of their treatment in order to manage their metastatic bone disease.Zoledronic acid inhibits osteoclastic bone resorption, which occurs at an accelerated pace due to the presence of tumor cells in the bone microenvironment. 1 Nitrogen-containing bisphosphonates affect osteoclast action by inhibition of enzymes of the mevalonate pathway. 2 Target enzymes include farnesyl pyrophosphate synthase 3,4 and/or geranylgeranylpyrophosphate synthase, 5 leading to a lack of formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These isoprenoids are requisite for posttranslation lipid modification (i.e., farnesylation and geranylgeranylation) of signaling GTPases, such as Ras, Rho and Rac. 6 As these control a variety of important osteoclast cell functions, their loss ultimately leads to osteoclast apoptosis through caspase-3 enzyme activation. 7 In addition to their inhibitory effect on osteocl...

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Bisphosphonates Are Incorporated into Adenine Nucleotides by Human Aminoacyl-tRNA Synthetase Enzymes

Cited by 105 publications

References 0 publications

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

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

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

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