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Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.

García-Beccaria M, Martínez P, Méndez-Pertuz M, Martínez S, Blanco-Aparicio C, Cañamero M, Mulero F, Ambrogio C, Flores JM, Megias D, Barbacid M, Pastor J, Blasco MA - EMBO Mol Med (2015)

Bottom Line: This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest.Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function.Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

View Article: PubMed Central - PubMed

Affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

No MeSH data available.


Related in: MedlinePlus

“In vivo” treatment with ETP-47037 compound blocks the progression of lung carcinomaSchematic representation of the ETP-47037 treatment protocol. Mice with already developed lung carcinomas were subjected to computerized tomography (CT) measurements before the start of the treatment. ETP-47037 was given at a dose of 75 mg/kg body weight by oral gavage 8 days out of the ten that the experiment lasted as indicated. At the end of the treatment, a CT was performed for quantification of tumor area and mice were sacrificed for further histological and molecular analysis. Control mice were similarly treated with vehicle.Quantification of tumor growth relative to initial tumor size. Representative CT images are shown to the right. The white arrowhead indicates a tumor within a highly inflammatory region.Quantification of TRF1 levels by immunofluorescence in intestine and lung tumors samples of mice treated with vehicle or with ETP-47037 for 10 days. Representative images are shown to the right (n = 4).Number of cells showing γH2AX foci in intestine and lung tumors samples of mice treated with vehicle or with ETP-47037 for 10 days. Representative images are shown to the right (n = 4).Data information: The data represent the mean values obtained from three mice in each group. Error bars represent standard errors. t-test was used to assess statistical significance.
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fig08: “In vivo” treatment with ETP-47037 compound blocks the progression of lung carcinomaSchematic representation of the ETP-47037 treatment protocol. Mice with already developed lung carcinomas were subjected to computerized tomography (CT) measurements before the start of the treatment. ETP-47037 was given at a dose of 75 mg/kg body weight by oral gavage 8 days out of the ten that the experiment lasted as indicated. At the end of the treatment, a CT was performed for quantification of tumor area and mice were sacrificed for further histological and molecular analysis. Control mice were similarly treated with vehicle.Quantification of tumor growth relative to initial tumor size. Representative CT images are shown to the right. The white arrowhead indicates a tumor within a highly inflammatory region.Quantification of TRF1 levels by immunofluorescence in intestine and lung tumors samples of mice treated with vehicle or with ETP-47037 for 10 days. Representative images are shown to the right (n = 4).Number of cells showing γH2AX foci in intestine and lung tumors samples of mice treated with vehicle or with ETP-47037 for 10 days. Representative images are shown to the right (n = 4).Data information: The data represent the mean values obtained from three mice in each group. Error bars represent standard errors. t-test was used to assess statistical significance.

Mentions: Mice with already developed p53- lung carcinomas were treated by oral gavage during 10 days (8 days in total with a 2-day gap) with 75 mg/kg body weight of ETP-47037. Control mice were similarly treated with vehicle. Previously to the start and at the end of the treatment, mice were subjected to computerized tomography (CT) for quantification of tumor growth area. Strikingly, 10 days of treatment with this compound effectively impaired the progression of already formed lung carcinomas compared to the group treated with vehicle (Fig8A and B). Of note, one of the tumors detected before the treatment was located in a highly inflammatory region, and for this reason, we could not accurately determine its size before the treatment (white arrowhead in Fig8B). TRF1 foci levels were significantly decreased in tumor samples as well as in intestines of mice treated with ETP-47037 compared to the vehicle (Fig8C). Decrease in TRF1 foci signal was accompanied with a significant increase in γH2AX-positive cells in both intestines and lung tumors (Fig8D). In addition, ET-47037-treated tumors showed a significant decrease in proliferating and mitotic cells and increase in the number of G2-arrested cells (Fig9A–D). Importantly, during the treatment, the mice showed a normal viability and did not show any signs of sickness. Histopathological analysis of the intestine did not reveal any apparent lesion although we saw increased aberrant mitotic figures and nuclei characteristic of TRF1 inhibition (Fig9E). In bone marrow, moderate aplasia, necrotic cells, and hemosiderosis were observed. In the skin, multinucleated cells and giant nuclei were detected (Fig9F), a hallmark of TRF1 targeting. Of note, ETP-47037 did not induce changes in telomere length in treated tumors as compared to untreated ones (Fig9G). These findings indicate that TRF1 inhibition can be achieved in vivo using chemical compounds and that there is a therapeutic window for targeting TRF1 in cancer that merits further work.


Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage.

García-Beccaria M, Martínez P, Méndez-Pertuz M, Martínez S, Blanco-Aparicio C, Cañamero M, Mulero F, Ambrogio C, Flores JM, Megias D, Barbacid M, Pastor J, Blasco MA - EMBO Mol Med (2015)

“In vivo” treatment with ETP-47037 compound blocks the progression of lung carcinomaSchematic representation of the ETP-47037 treatment protocol. Mice with already developed lung carcinomas were subjected to computerized tomography (CT) measurements before the start of the treatment. ETP-47037 was given at a dose of 75 mg/kg body weight by oral gavage 8 days out of the ten that the experiment lasted as indicated. At the end of the treatment, a CT was performed for quantification of tumor area and mice were sacrificed for further histological and molecular analysis. Control mice were similarly treated with vehicle.Quantification of tumor growth relative to initial tumor size. Representative CT images are shown to the right. The white arrowhead indicates a tumor within a highly inflammatory region.Quantification of TRF1 levels by immunofluorescence in intestine and lung tumors samples of mice treated with vehicle or with ETP-47037 for 10 days. Representative images are shown to the right (n = 4).Number of cells showing γH2AX foci in intestine and lung tumors samples of mice treated with vehicle or with ETP-47037 for 10 days. Representative images are shown to the right (n = 4).Data information: The data represent the mean values obtained from three mice in each group. Error bars represent standard errors. t-test was used to assess statistical significance.
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Related In: Results  -  Collection

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fig08: “In vivo” treatment with ETP-47037 compound blocks the progression of lung carcinomaSchematic representation of the ETP-47037 treatment protocol. Mice with already developed lung carcinomas were subjected to computerized tomography (CT) measurements before the start of the treatment. ETP-47037 was given at a dose of 75 mg/kg body weight by oral gavage 8 days out of the ten that the experiment lasted as indicated. At the end of the treatment, a CT was performed for quantification of tumor area and mice were sacrificed for further histological and molecular analysis. Control mice were similarly treated with vehicle.Quantification of tumor growth relative to initial tumor size. Representative CT images are shown to the right. The white arrowhead indicates a tumor within a highly inflammatory region.Quantification of TRF1 levels by immunofluorescence in intestine and lung tumors samples of mice treated with vehicle or with ETP-47037 for 10 days. Representative images are shown to the right (n = 4).Number of cells showing γH2AX foci in intestine and lung tumors samples of mice treated with vehicle or with ETP-47037 for 10 days. Representative images are shown to the right (n = 4).Data information: The data represent the mean values obtained from three mice in each group. Error bars represent standard errors. t-test was used to assess statistical significance.
Mentions: Mice with already developed p53- lung carcinomas were treated by oral gavage during 10 days (8 days in total with a 2-day gap) with 75 mg/kg body weight of ETP-47037. Control mice were similarly treated with vehicle. Previously to the start and at the end of the treatment, mice were subjected to computerized tomography (CT) for quantification of tumor growth area. Strikingly, 10 days of treatment with this compound effectively impaired the progression of already formed lung carcinomas compared to the group treated with vehicle (Fig8A and B). Of note, one of the tumors detected before the treatment was located in a highly inflammatory region, and for this reason, we could not accurately determine its size before the treatment (white arrowhead in Fig8B). TRF1 foci levels were significantly decreased in tumor samples as well as in intestines of mice treated with ETP-47037 compared to the vehicle (Fig8C). Decrease in TRF1 foci signal was accompanied with a significant increase in γH2AX-positive cells in both intestines and lung tumors (Fig8D). In addition, ET-47037-treated tumors showed a significant decrease in proliferating and mitotic cells and increase in the number of G2-arrested cells (Fig9A–D). Importantly, during the treatment, the mice showed a normal viability and did not show any signs of sickness. Histopathological analysis of the intestine did not reveal any apparent lesion although we saw increased aberrant mitotic figures and nuclei characteristic of TRF1 inhibition (Fig9E). In bone marrow, moderate aplasia, necrotic cells, and hemosiderosis were observed. In the skin, multinucleated cells and giant nuclei were detected (Fig9F), a hallmark of TRF1 targeting. Of note, ETP-47037 did not induce changes in telomere length in treated tumors as compared to untreated ones (Fig9G). These findings indicate that TRF1 inhibition can be achieved in vivo using chemical compounds and that there is a therapeutic window for targeting TRF1 in cancer that merits further work.

Bottom Line: This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest.Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function.Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

View Article: PubMed Central - PubMed

Affiliation: Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.

No MeSH data available.


Related in: MedlinePlus