Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite

Makkonen, Niina; Salminen, Antero; Rogers, Michael J.; Frith, Julie C.; Urtti, Arto; Azhayeva, Elena; Mönkkönen, Jukka

doi:10.1016/s0928-0987(98)00065-7

Cited by 93 publications

(58 citation statements)

References 39 publications

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“…In our study, clodronate suppressed cell growth and production of proinflammatory cytokines in Thena-Nu cells in a dose-and time-dependent manner. Dosedependent reduction of NK-kB activity in Thena-Nu cells following clodronate treatment was demonstrated by western blotting (data not shown), suggesting that suppression of NF-kB activity may also be involved in clodronate-induced growth and cytokine inhibitory effects (Makkonen et al 1999).…”

Section: Discussionmentioning

confidence: 94%

“…This incorporation may result in inhibition of tRNA aminoacylation by these enzymes, leading to inhibition of protein synthesis (Rogers et al 1996, Frith et al 1997. Clodronate was demonstrated to downregulate the production of IL-6 and TNF-a (Monkkonen et al 1994), as well as NF-kB activation (Makkonen et al 1999) in mouse macrophage-like RAW264 cells stimulated with lipopolysaccharides; inhibition of IL-6 production by osteosarcoma MG-63 cells was also documented (Giuliani et al 1998). Cancer patients receiving clodronate treatment showed reduction in serum IL-6 levels, which was not associated with cytotoxic effects (Sauty et al 1996).…”

Section: Introductionmentioning

confidence: 97%

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Clodronate alleviates cachexia and prolongs survival in nude mice xenografted with an anaplastic thyroid carcinoma cell line

Wang

Shen

Hsieh

et al. 2006

Journal of Endocrinology

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Cancer cachexia is one of the most common manifestations of advanced malignant disease and is frequently associated with decreased survival. Previously, we reported the establishment of a new anaplastic thyroid carcinoma cell line, Thena, and its mouse xenograft, Thena-Nu, which induced cachexia in athymic nude mice. Subsequent studies showed that the addition of clodronate to Thena-Nu cultures reduced cell proliferation as well as cytokine production in a dose-and timedependent manner. Weekly administration of clodronate induced tumor cytostasis, attenuation of cachexia, as well as prolongation of survival in Thena-Nu-bearing mice. Reduced serum interleukin 6, tumor necrosis factor-a, and granulocyte colony stimulating factor levels were detected, whereas, serum leukemia inhibitory factor levels were not reduced. Liver necrosis, observed in tumor-bearing mice, was also improved following clodronate treatment. Discontinuation of clodronate treatment, however, resulted in progressive tumor growth and weight loss. Our results demonstrated that clodronate could exert therapeutic efficacy on amelioration of cancer cachexia in the hosts. Nevertheless, this study also points out that a longer period of treatment is required to maintain these effects.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 97%

Clodronate alleviates cachexia and prolongs survival in nude mice xenografted with an anaplastic thyroid carcinoma cell line

Wang

Shen

Hsieh

et al. 2006

Journal of Endocrinology

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“…It is not completely understood how the JAK-STAT pathway and NF-B family members interact to regulate TNF-␣ gene expression. Recent reports suggest that bisphosphonates have important effects on macrophages (11,33). One of these effects is thought to be activation of the NF-B pathway to increase production of TNF-␣ by macrophages (33).…”

mentioning

confidence: 99%

“…Recent reports suggest that bisphosphonates have important effects on macrophages (11,33). One of these effects is thought to be activation of the NF-B pathway to increase production of TNF-␣ by macrophages (33). However, the molecular mechanism by which bisphosphonates modulate the cytokine network is not fully understood.…”

mentioning

confidence: 99%

Modulation of TNF-α Gene Expression by IFN-γ and Pamidronate in Murine Macrophages: Regulation by STAT1-Dependent Pathways

Takagi

Kanangat

et al. 2005

The Journal of Immunology

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Aminobisphosphonates are drugs used in the treatment of hypercalcemia, Paget’s disease, osteoporosis, and malignancy. Some patients treated with aminobisphosphonates have a transient febrile reaction that may be caused by an increased serum concentration of proinflammatory cytokines. Aminobisphosphonates induce the production of certain proinflammatory cytokines in vitro, especially in cells of monocytic lineage. A unique feature of aminobisphosphonates is that they bind the Vγ2Vδ2 class of T cells, which are found only in primates, and stimulate cytokine production. The effects of aminobisphosphonates on other cells, including macrophages, are incompletely understood. We show in this study that treatment of murine macrophages with pamidronate, a second generation aminobisphosphonate, induces TNF-α production. Furthermore, pretreatment of murine macrophages with pamidronate before stimulation with IFN-γ significantly augments IFN-γ-dependent production of TNF-α. This pamidronate-mediated augmentation of TNF-α production results in sustained phosphorylation of the tyrosine residue at position 701 of STAT1 after IFN-γ treatment. Our data suggest that this sustained phosphorylation results from inhibition of protein tyrosine phosphatase activity. We also show that pamidronate treatment increases TNF-α production in vivo in mice. Pamidronate-augmented TNF-α production by macrophages might be a useful strategy for cytokine-based anticancer therapy.

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“…Em razão de sua propriedade anti-reabsortiva, os BFs também estão sendo investigados como inibidores da destruição das articulações, com possível uso no tratamento da artrite reumatóide (AR). Adicionalmente à sua capacidade de inibir a reabsorção óssea, mostraram atividade antiinflamatória em modelos animais de AR, bem como em humanos 23 .…”

Section: Introductionunclassified

Bifosfonatos (BFs) como transportadores osteotrópicos no planejamento de fármacos dirigidos

Castro¹,

Silva²,

Chin³

et al. 2004

Quím. Nova

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Recebido em 14/4/03; aceito em 21/10/03 BISPHOSPHONATES AS OSTEOTROPIC CARRIERS FOR DESIGNING SITE-DIRECTED DRUGS. Drug therapy involving bone tissue diseases is difficult, calling for the design of specific drugs. The present paper is a brief review of a new site-directed system termed ODDS (osteotropic drug delivery system), based on a latenciation process, using bisphosphonates as bone carriers. This is an important tool for the rational prodrug design for obtaining selective drugs.Keywords: bisphosphonates; prodrugs; ODDS. INTRODUÇÃOA liberação seletiva de fármacos no local de ação via pró-fármacos tem gerado interesse considerável para aumentar a potência e diminuir os efeitos adversos dos protótipos dos quais derivam. Embora muitas formas de pró-fármacos seletivos tenham sido desenvolvidas, o tecido ósseo ainda permanecia como um alvo limitado, devido às suas propriedades biológicas e à falta de um sistema circulatório semelhante ao de outros tecidos 1 . O tecido ósseo adulto é distinguido de outros tecidos pela presença de fosfato e cálcio mineral, como a hidroxiapatita [Ca 10 (PO 4 ) 6 (OH) 2 ], que incorpora em sua estrutura outros íons e sais, sendo o principal componente mineral constituinte do osso e o elemento essencial responsável pela função de apoio mecânico 2-4 . Devido à dinâmica do tecido ósseo, este é continuamente desgastado pela atividade osteoclástica e substituído pela atividade osteoblástica, ambas reguladas por fatores sistêmicos e locais [5][6] . Como qualquer outro tecido, os ossos são suscetíveis a doenças que influenciam a atividade osteoclástica, como o hiperparatiroidismo e câncer, sendo a hipercalcemia resultado de destruição direta e localizada do tecido ósseo por células neoplásicas 7 . Exemplos primá-rios são a artrite reumatóide (AR) e a lesão espinhal, nas quais se observa a perda gradual e rápida de massa óssea 8,9 . Recentemente, propôs-se um novo e promissor sistema de liberação de fármacos para atingir o tecido ósseo via pró-fármacos denominado "Osteotropic Drug Delivery System (ODDS)", que utiliza os bifosfonatos como transportadores 10 . Os bifosfonatos (BFs) são conhecidos por sua alta afinidade pela hidroxiapatita. Esta propriedade trópica óssea dos BFs possibilitou sua utilização no planejamento de formas latentes de liberação de fármacos nas estruturas ósseas ou na medula óssea 1 . Os pirofosfatos (P-O-P) são reguladores fisiológicos da calcificação e reabsorção óssea, naturalmente presentes no soro e na urina. A ação dos bifosfonatos deve-se à sua semelhança estrutural com este grupo de compostos 11-13 (Figura 1).O trabalho nesta área tem-se concentrado na liberação de radioisótopos, mas, atualmente, as pesquisas compreendem a liberação de outras moléculas, cuja atividade farmacológica é bem definida. Estas incluem agentes antineoplásicos, anabolizantes, antiinflamatórios e, recentemente, proteínas 4 .A descoberta de que os BFs podiam inibir a reabsorção óssea foi realizada em 1960, após tentativas para identificar agentes que fossem semelhantes ao pirofosfato e q...

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Contrasting effects of alendronate and clodronate on RAW 264 macrophages: the role of a bisphosphonate metabolite

Cited by 93 publications

References 39 publications

Clodronate alleviates cachexia and prolongs survival in nude mice xenografted with an anaplastic thyroid carcinoma cell line

Clodronate alleviates cachexia and prolongs survival in nude mice xenografted with an anaplastic thyroid carcinoma cell line

Modulation of TNF-α Gene Expression by IFN-γ and Pamidronate in Murine Macrophages: Regulation by STAT1-Dependent Pathways

Bifosfonatos (BFs) como transportadores osteotrópicos no planejamento de fármacos dirigidos

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