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Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases.

Lamora A, Mullard M, Amiaud J, Brion R, Heymann D, Redini F, Verrecchia F - Oncotarget (2015)

Bottom Line: In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development.In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis.Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment.

View Article: PubMed Central - PubMed

Affiliation: INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.

ABSTRACT
Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because we recently demonstrated that TGF-β/Smad cascade plays a crucial role in osteosarcoma metastatic progression, we investigated the effect of halofuginone, identified as an inhibitor of the TGF-β/Smad3 cascade, on osteosarcoma progression. A preclinical model of osteosarcoma was used to evaluate the impact of halofuginone on tumor growth, tumor microenvironment and metastasis development. In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that halofuginone decreases cell viability mainly by its ability to induce caspase-3 dependent cell apoptosis. Moreover, halofuginone inhibits the TGF-β/Smad3 cascade and the response of TGF-β key targets involved in the metastases dissemination process such as MMP-2. In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis. Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment. Using halofuginone may be a promising therapeutic strategy against tumor progression of osteosarcoma specifically against lung metastases dissemination.

No MeSH data available.


Related in: MedlinePlus

Halofuginone inhibits osteosarcoma primary tumor growthA. Mice were injected with 2.106 HOS cells in each group. One day after cell injection, mice were daily intraperitoneal injected with 0.2 μg/mouse (n = 4), 0.5 μg/mouse (n = 4), 1 μg/mouse (n = 10) or 5 μg/mouse (n = 10) halofuginone or with vehicle (control group, n = 10). The results are representative of 2 independent experiments. The mean tumor volumes were calculated from day 1 to day 30. (Mean ± SEM; ***p < 0.005). B. Tumor samples (tumor sizes around 500 mm3) were fixed, embedded in paraffin, sectioned and stained with Ki-67. Representative photomicrographs per group are shown. C. Tumor samples (tumor sizes around 500 mm3) were fixed, embedded in paraffin, sectioned and stained with Caspase-3. Representative photomicrographs per group are shown.
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Figure 1: Halofuginone inhibits osteosarcoma primary tumor growthA. Mice were injected with 2.106 HOS cells in each group. One day after cell injection, mice were daily intraperitoneal injected with 0.2 μg/mouse (n = 4), 0.5 μg/mouse (n = 4), 1 μg/mouse (n = 10) or 5 μg/mouse (n = 10) halofuginone or with vehicle (control group, n = 10). The results are representative of 2 independent experiments. The mean tumor volumes were calculated from day 1 to day 30. (Mean ± SEM; ***p < 0.005). B. Tumor samples (tumor sizes around 500 mm3) were fixed, embedded in paraffin, sectioned and stained with Ki-67. Representative photomicrographs per group are shown. C. Tumor samples (tumor sizes around 500 mm3) were fixed, embedded in paraffin, sectioned and stained with Caspase-3. Representative photomicrographs per group are shown.

Mentions: To investigate the effect of halofuginone on osteosarcoma progression, we firstly used a mice preclinical experimental model of osteosarcoma induced by paratibial injection of HOS cells that mimics the human disease. As shown in Fig. 1A, the treatment of mice with halofuginone significantly inhibited the tumor growth in dose dependent manner. The mean tumor size at day 30 was 2524.3 ± 12.5 mm3, 2891.1 ± 54.5 mm3, 1949.8 ± 154.5 mm3, 1336.6 ± 50.8 mm3 and 1329.1 ± 70.1 mm3 when the mice were treated respectively with vehicle (control group) or with 0.2 μg/day, 0.5 μg/day, 1 μg/day or 5 μg/day of halofuginone. In this context, immunohistochemical staining for the proliferative marker Ki67 in mice tumor samples showed that halofuginone treatment decreases tumor cell proliferation (Fig. 1B) during the first stage of tumor development (tumor sizes around 500 mm3). In addition, immunohistochemical staining for the apoptotic marker caspase-3 in the same samples showed that the treatment of mice with halofuginone increases tumor cell apoptosis (Fig. 1C).


Anticancer activity of halofuginone in a preclinical model of osteosarcoma: inhibition of tumor growth and lung metastases.

Lamora A, Mullard M, Amiaud J, Brion R, Heymann D, Redini F, Verrecchia F - Oncotarget (2015)

Halofuginone inhibits osteosarcoma primary tumor growthA. Mice were injected with 2.106 HOS cells in each group. One day after cell injection, mice were daily intraperitoneal injected with 0.2 μg/mouse (n = 4), 0.5 μg/mouse (n = 4), 1 μg/mouse (n = 10) or 5 μg/mouse (n = 10) halofuginone or with vehicle (control group, n = 10). The results are representative of 2 independent experiments. The mean tumor volumes were calculated from day 1 to day 30. (Mean ± SEM; ***p < 0.005). B. Tumor samples (tumor sizes around 500 mm3) were fixed, embedded in paraffin, sectioned and stained with Ki-67. Representative photomicrographs per group are shown. C. Tumor samples (tumor sizes around 500 mm3) were fixed, embedded in paraffin, sectioned and stained with Caspase-3. Representative photomicrographs per group are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4546476&req=5

Figure 1: Halofuginone inhibits osteosarcoma primary tumor growthA. Mice were injected with 2.106 HOS cells in each group. One day after cell injection, mice were daily intraperitoneal injected with 0.2 μg/mouse (n = 4), 0.5 μg/mouse (n = 4), 1 μg/mouse (n = 10) or 5 μg/mouse (n = 10) halofuginone or with vehicle (control group, n = 10). The results are representative of 2 independent experiments. The mean tumor volumes were calculated from day 1 to day 30. (Mean ± SEM; ***p < 0.005). B. Tumor samples (tumor sizes around 500 mm3) were fixed, embedded in paraffin, sectioned and stained with Ki-67. Representative photomicrographs per group are shown. C. Tumor samples (tumor sizes around 500 mm3) were fixed, embedded in paraffin, sectioned and stained with Caspase-3. Representative photomicrographs per group are shown.
Mentions: To investigate the effect of halofuginone on osteosarcoma progression, we firstly used a mice preclinical experimental model of osteosarcoma induced by paratibial injection of HOS cells that mimics the human disease. As shown in Fig. 1A, the treatment of mice with halofuginone significantly inhibited the tumor growth in dose dependent manner. The mean tumor size at day 30 was 2524.3 ± 12.5 mm3, 2891.1 ± 54.5 mm3, 1949.8 ± 154.5 mm3, 1336.6 ± 50.8 mm3 and 1329.1 ± 70.1 mm3 when the mice were treated respectively with vehicle (control group) or with 0.2 μg/day, 0.5 μg/day, 1 μg/day or 5 μg/day of halofuginone. In this context, immunohistochemical staining for the proliferative marker Ki67 in mice tumor samples showed that halofuginone treatment decreases tumor cell proliferation (Fig. 1B) during the first stage of tumor development (tumor sizes around 500 mm3). In addition, immunohistochemical staining for the apoptotic marker caspase-3 in the same samples showed that the treatment of mice with halofuginone increases tumor cell apoptosis (Fig. 1C).

Bottom Line: In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development.In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis.Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment.

View Article: PubMed Central - PubMed

Affiliation: INSERM, UMR 957, Equipe Labellisée Ligue contre le Cancer 2012, Nantes, France.

ABSTRACT
Osteosarcoma is the main malignant primary bone tumor in children and adolescents for whom the prognosis remains poor, especially when metastases are present at diagnosis. Because we recently demonstrated that TGF-β/Smad cascade plays a crucial role in osteosarcoma metastatic progression, we investigated the effect of halofuginone, identified as an inhibitor of the TGF-β/Smad3 cascade, on osteosarcoma progression. A preclinical model of osteosarcoma was used to evaluate the impact of halofuginone on tumor growth, tumor microenvironment and metastasis development. In vivo experiments showed that halofuginone reduces primary tumor growth and lung metastases development. In vitro experiments demonstrated that halofuginone decreases cell viability mainly by its ability to induce caspase-3 dependent cell apoptosis. Moreover, halofuginone inhibits the TGF-β/Smad3 cascade and the response of TGF-β key targets involved in the metastases dissemination process such as MMP-2. In addition, halofuginone treatment affects the "vicious cycle" established between tumor and bone cells, and therefore the tumor-associated bone osteolysis. Together, these results demonstrate that halofuginone decreased primary osteosarcoma development and associated lung metastases by targeting both the tumor cells and the tumor microenvironment. Using halofuginone may be a promising therapeutic strategy against tumor progression of osteosarcoma specifically against lung metastases dissemination.

No MeSH data available.


Related in: MedlinePlus