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dc.contributor.author
Wan, Xinhai
dc.contributor.author
Li, Zhi-Gang
dc.contributor.author
Yingling, Jonathan M.
dc.contributor.author
Yang, Jun
dc.contributor.author
Starbuck, Michael W.
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Ravoori, Murali K.
dc.contributor.author
Kundra, Vikas
dc.contributor.author
Vazquez, Elba Susana
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dc.contributor.author
Navone, Nora
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dc.date.available
2020-01-27T19:20:56Z
dc.date.issued
2012-03
dc.identifier.citation
Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M.; Yang, Jun; Starbuck, Michael W.; et al.; Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth; Elsevier Science Inc; Bone; 50; 3; 3-2012; 695-703
dc.identifier.issn
8756-3282
dc.identifier.uri
http://hdl.handle.net/11336/95879
dc.description.abstract
Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6. weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth in bone. Thus, targeting TGF-β receptor I is a valuable intervention in men with advanced PCa.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Elsevier Science Inc
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
BONE METASTASES
dc.subject
PROSTATE CANCER
dc.subject
TGF-Β
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TGF-Β RECEPTOR TYPE I KINASE INHIBITOR
dc.subject.classification
Oncología
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dc.subject.classification
Medicina Clínica
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dc.subject.classification
CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2019-11-08T15:08:55Z
dc.journal.volume
50
dc.journal.number
3
dc.journal.pagination
695-703
dc.journal.pais
Países Bajos
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dc.journal.ciudad
Amsterdam
dc.description.fil
Fil: Wan, Xinhai. University of Texas; Estados Unidos
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Fil: Li, Zhi-Gang. University of Texas; Estados Unidos
dc.description.fil
Fil: Yingling, Jonathan M.. Eli Lilly And Company; Estados Unidos
dc.description.fil
Fil: Yang, Jun. University of Texas; Estados Unidos
dc.description.fil
Fil: Starbuck, Michael W.. University of Texas; Estados Unidos
dc.description.fil
Fil: Ravoori, Murali K.. University of Texas; Estados Unidos
dc.description.fil
Fil: Kundra, Vikas. University of Texas; Estados Unidos
dc.description.fil
Fil: Vazquez, Elba Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
dc.description.fil
Fil: Navone, Nora. University of Texas; Estados Unidos
dc.journal.title
Bone
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S8756328211013615
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/https://doi.org/10.1016/j.bone.2011.11.022
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