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Erlotinib inhibits osteolytic bone invasion of human non-small-cell lung cancer cell line NCI-H292.

Furugaki K, Moriya Y, Iwai T, Yorozu K, Yanagisawa M, Kondoh K, Fujimoto-Ohuchi K, Mori K - Clin. Exp. Metastasis (2011)

Bottom Line: In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction.Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro.In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

View Article: PubMed Central - PubMed

Affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kajiwara, Kamakura, Kanagawa, Japan.

ABSTRACT
Previous preclinical and clinical findings have suggested a potential role of epidermal growth factor receptor (EGFR) in osteoclast differentiation and the pathogenesis of bone metastasis in cancer. In this study, we investigated the effect of erlotinib, an orally active EGFR tyrosine kinase inhibitor (TKI), on the bone invasion of human non-small-cell lung cancer (NSCLC) cell line NCI-H292. First, we established a novel osteolytic bone invasion model of NCI-H292 cells which was made by inoculating cancer cells into the tibia of scid mice. In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction. Erlotinib treatment suppressed osteoclast activation to the basal level through suppressing receptor activator of NF-κB ligand (RANKL) expression in osteoblast/stromal cell at the bone metastatic sites, which leads to inhibition of osteolytic bone destruction caused by NCI-H292 cells. Erlotinib inhibited the proliferation of NCI-H292 cells in in vitro. Erlotinib suppressed the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), IL-8, IL-11 and vascular endothelial growth factor (VEGF) in NCI-H292 cells. Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro. In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

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Effects of erlotinib on production of osteolytic factor of NCI-H292 cells. The protein levels of osteolytic factors in the conditioned media of NCI-H292 cells treated with or without 1 μM erlotinib were measured. Each point represents the mean + SD of duplicates
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Fig4: Effects of erlotinib on production of osteolytic factor of NCI-H292 cells. The protein levels of osteolytic factors in the conditioned media of NCI-H292 cells treated with or without 1 μM erlotinib were measured. Each point represents the mean + SD of duplicates

Mentions: To elucidate the soluble factor from NCI-H292 cells which is related to RANKL expression in osteoblasts/ST2 cells, we investigated the production of major osteolytic factors including PTHrP, IL-6 and IL-8 etc. As a result, NCI-H292 cells produced a sufficient amount of PTHrP, IL-6, IL-8, IL-11 and VEGF but the production of IL-1β, IL-10, GM-CSF and TNF-α was lower than the detection limit (data not shown). Erlotinib blocked the production of PTHrP, IL-8, IL-11 and VEGF in NCI-H292 cells in a dose-dependent manner (Fig. 4). Meanwhile, IL-6 production was not changed by erlotinib treatment, indicating that IL-6 expression is independent of the EGFR signal in NCI-H292 cells (Fig. 4).Fig. 4


Erlotinib inhibits osteolytic bone invasion of human non-small-cell lung cancer cell line NCI-H292.

Furugaki K, Moriya Y, Iwai T, Yorozu K, Yanagisawa M, Kondoh K, Fujimoto-Ohuchi K, Mori K - Clin. Exp. Metastasis (2011)

Effects of erlotinib on production of osteolytic factor of NCI-H292 cells. The protein levels of osteolytic factors in the conditioned media of NCI-H292 cells treated with or without 1 μM erlotinib were measured. Each point represents the mean + SD of duplicates
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198194&req=5

Fig4: Effects of erlotinib on production of osteolytic factor of NCI-H292 cells. The protein levels of osteolytic factors in the conditioned media of NCI-H292 cells treated with or without 1 μM erlotinib were measured. Each point represents the mean + SD of duplicates
Mentions: To elucidate the soluble factor from NCI-H292 cells which is related to RANKL expression in osteoblasts/ST2 cells, we investigated the production of major osteolytic factors including PTHrP, IL-6 and IL-8 etc. As a result, NCI-H292 cells produced a sufficient amount of PTHrP, IL-6, IL-8, IL-11 and VEGF but the production of IL-1β, IL-10, GM-CSF and TNF-α was lower than the detection limit (data not shown). Erlotinib blocked the production of PTHrP, IL-8, IL-11 and VEGF in NCI-H292 cells in a dose-dependent manner (Fig. 4). Meanwhile, IL-6 production was not changed by erlotinib treatment, indicating that IL-6 expression is independent of the EGFR signal in NCI-H292 cells (Fig. 4).Fig. 4

Bottom Line: In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction.Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro.In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

View Article: PubMed Central - PubMed

Affiliation: Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kajiwara, Kamakura, Kanagawa, Japan.

ABSTRACT
Previous preclinical and clinical findings have suggested a potential role of epidermal growth factor receptor (EGFR) in osteoclast differentiation and the pathogenesis of bone metastasis in cancer. In this study, we investigated the effect of erlotinib, an orally active EGFR tyrosine kinase inhibitor (TKI), on the bone invasion of human non-small-cell lung cancer (NSCLC) cell line NCI-H292. First, we established a novel osteolytic bone invasion model of NCI-H292 cells which was made by inoculating cancer cells into the tibia of scid mice. In this model, NCI-H292 cells markedly activated osteoclasts in tibia, which resulted in osteolytic bone destruction. Erlotinib treatment suppressed osteoclast activation to the basal level through suppressing receptor activator of NF-κB ligand (RANKL) expression in osteoblast/stromal cell at the bone metastatic sites, which leads to inhibition of osteolytic bone destruction caused by NCI-H292 cells. Erlotinib inhibited the proliferation of NCI-H292 cells in in vitro. Erlotinib suppressed the production of osteolytic factors, such as parathyroid hormone-related protein (PTHrP), IL-8, IL-11 and vascular endothelial growth factor (VEGF) in NCI-H292 cells. Furthermore, erlotinib also inhibited osteoblast/stromal cell proliferation in vitro and the development of osteoclasts induced by RANKL in vitro. In conclusion, erlotinib inhibits tumor-induced osteolytic invasion in bone metastasis by suppressing osteoclast activation through inhibiting tumor growth at the bone metastatic sites, osteolytic factor production in tumor cells, osteoblast/stromal cell proliferation and osteoclast differentiation from mouse bone marrow cells.

Show MeSH
Related in: MedlinePlus