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Metformin Induced AMPK Activation, G0/G1 Phase Cell Cycle Arrest and the Inhibition of Growth of Esophageal Squamous Cell Carcinomas In Vitro and In Vivo.

Cai X, Hu X, Tan X, Cheng W, Wang Q, Chen X, Guan Y, Chen C, Jing X - PLoS ONE (2015)

Bottom Line: Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1.Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo.In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.

ABSTRACT
Esophageal squamous cell carcinomas (ESCC) have become a severe threat to health and the current treatments for ESCC are frequently not effective. Recent epidemiological studies suggest that the anti-hyperglycemic agent metformin may reduce the risk of developing cancer, including ESCC, among diabetic patients. However, the antitumor effects of metformin on ESCC and the mechanisms underlying its cell cycle regulation remain elusive. The findings reported herein show that the anti-proliferative action of metformin on ESCC cell lines is partially mediated by AMPK. Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1. In vivo experiments further showed that metformin inhibited tumor growth in a ESCC xenograft model. Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo. In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model. AMPK, p53, p21CIP1, p27KIP1 and cyclinD1 are involved in the inhibition of tumor growth that is induced by metformin and cell cycle arrest in ESCC. These findings indicate that metformin has the potential for use in the treatment of ESCC.

No MeSH data available.


Related in: MedlinePlus

Metformin inhibited the growth of EC109 cell xenografts in nude mice.Xenografts were generated by the subcutaneous implantation of EC109 cells. Two weeks later, physiological saline (control) or metformin (250 mg/kg) were intragastrically administered and the feeding continued until the end of the study. Tumor volumes were measured every 2 days. (A) Photographs showing the representative xenograft tumors on metformin-treated or vehicle-treated nude mice (bar = 1centimetre). (B) Average tumor volumes of the EC109 cell xenografts. (C) Paraffin sections of excised tumors were assessed by H&E stain showing large necrosis area in both experiment and control groups. In necrotic area there were very few nuclei that were well stained by hematoxylin, and tissue was disintegrating and the morphologic details were not preserved (200× magnification; bar = 100 microns). (D) The body weight of all mice were measured the day before intragastric administration, and before euthanasia. Histograms show the average weight from the different groups. There was no difference before and after intragastric administration. (E) After intragastric administration, water and food were withdrawn.for 3h. The serum glucose was detected by blood glucose monitor. The serum glucose levels were not statistically different between the control and treated groups. Data represent mean ± SE. Tre: metformin treated group; Con: control group (n = 10; * P<0.05; ** P< 0.01; NS: no significance; vs. control).
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pone.0133349.g005: Metformin inhibited the growth of EC109 cell xenografts in nude mice.Xenografts were generated by the subcutaneous implantation of EC109 cells. Two weeks later, physiological saline (control) or metformin (250 mg/kg) were intragastrically administered and the feeding continued until the end of the study. Tumor volumes were measured every 2 days. (A) Photographs showing the representative xenograft tumors on metformin-treated or vehicle-treated nude mice (bar = 1centimetre). (B) Average tumor volumes of the EC109 cell xenografts. (C) Paraffin sections of excised tumors were assessed by H&E stain showing large necrosis area in both experiment and control groups. In necrotic area there were very few nuclei that were well stained by hematoxylin, and tissue was disintegrating and the morphologic details were not preserved (200× magnification; bar = 100 microns). (D) The body weight of all mice were measured the day before intragastric administration, and before euthanasia. Histograms show the average weight from the different groups. There was no difference before and after intragastric administration. (E) After intragastric administration, water and food were withdrawn.for 3h. The serum glucose was detected by blood glucose monitor. The serum glucose levels were not statistically different between the control and treated groups. Data represent mean ± SE. Tre: metformin treated group; Con: control group (n = 10; * P<0.05; ** P< 0.01; NS: no significance; vs. control).

Mentions: The in vitro results indicate that metformin induces the inhibition of ESCC cell growth by blocking the cell cycle; we further examined the growth-inhibitory effect of metformin in vivo. Nude mice were administered with Metformin or physiological saline after the subcutaneous implantation of EC109 cells. The findings showed that metformin effectively suppressed the growth of the ESCC xenografts (Fig 5A and 5B). Tumors in the treatment group ceased growing 12 days after the metformin treatment (26 days after implantation). At 28 days later (42 days after implantation), the tumor size in the treatment group began to decline, leading to a significant difference compared with that in the control group. Interestingly, even though the tumor sizes were much smaller in the case of the metformin treatment, a pathological evaluation showed that these tumors had a similar scale of necrotic areas (Fig 5C).


Metformin Induced AMPK Activation, G0/G1 Phase Cell Cycle Arrest and the Inhibition of Growth of Esophageal Squamous Cell Carcinomas In Vitro and In Vivo.

Cai X, Hu X, Tan X, Cheng W, Wang Q, Chen X, Guan Y, Chen C, Jing X - PLoS ONE (2015)

Metformin inhibited the growth of EC109 cell xenografts in nude mice.Xenografts were generated by the subcutaneous implantation of EC109 cells. Two weeks later, physiological saline (control) or metformin (250 mg/kg) were intragastrically administered and the feeding continued until the end of the study. Tumor volumes were measured every 2 days. (A) Photographs showing the representative xenograft tumors on metformin-treated or vehicle-treated nude mice (bar = 1centimetre). (B) Average tumor volumes of the EC109 cell xenografts. (C) Paraffin sections of excised tumors were assessed by H&E stain showing large necrosis area in both experiment and control groups. In necrotic area there were very few nuclei that were well stained by hematoxylin, and tissue was disintegrating and the morphologic details were not preserved (200× magnification; bar = 100 microns). (D) The body weight of all mice were measured the day before intragastric administration, and before euthanasia. Histograms show the average weight from the different groups. There was no difference before and after intragastric administration. (E) After intragastric administration, water and food were withdrawn.for 3h. The serum glucose was detected by blood glucose monitor. The serum glucose levels were not statistically different between the control and treated groups. Data represent mean ± SE. Tre: metformin treated group; Con: control group (n = 10; * P<0.05; ** P< 0.01; NS: no significance; vs. control).
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Related In: Results  -  Collection

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pone.0133349.g005: Metformin inhibited the growth of EC109 cell xenografts in nude mice.Xenografts were generated by the subcutaneous implantation of EC109 cells. Two weeks later, physiological saline (control) or metformin (250 mg/kg) were intragastrically administered and the feeding continued until the end of the study. Tumor volumes were measured every 2 days. (A) Photographs showing the representative xenograft tumors on metformin-treated or vehicle-treated nude mice (bar = 1centimetre). (B) Average tumor volumes of the EC109 cell xenografts. (C) Paraffin sections of excised tumors were assessed by H&E stain showing large necrosis area in both experiment and control groups. In necrotic area there were very few nuclei that were well stained by hematoxylin, and tissue was disintegrating and the morphologic details were not preserved (200× magnification; bar = 100 microns). (D) The body weight of all mice were measured the day before intragastric administration, and before euthanasia. Histograms show the average weight from the different groups. There was no difference before and after intragastric administration. (E) After intragastric administration, water and food were withdrawn.for 3h. The serum glucose was detected by blood glucose monitor. The serum glucose levels were not statistically different between the control and treated groups. Data represent mean ± SE. Tre: metformin treated group; Con: control group (n = 10; * P<0.05; ** P< 0.01; NS: no significance; vs. control).
Mentions: The in vitro results indicate that metformin induces the inhibition of ESCC cell growth by blocking the cell cycle; we further examined the growth-inhibitory effect of metformin in vivo. Nude mice were administered with Metformin or physiological saline after the subcutaneous implantation of EC109 cells. The findings showed that metformin effectively suppressed the growth of the ESCC xenografts (Fig 5A and 5B). Tumors in the treatment group ceased growing 12 days after the metformin treatment (26 days after implantation). At 28 days later (42 days after implantation), the tumor size in the treatment group began to decline, leading to a significant difference compared with that in the control group. Interestingly, even though the tumor sizes were much smaller in the case of the metformin treatment, a pathological evaluation showed that these tumors had a similar scale of necrotic areas (Fig 5C).

Bottom Line: Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1.Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo.In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515031, China.

ABSTRACT
Esophageal squamous cell carcinomas (ESCC) have become a severe threat to health and the current treatments for ESCC are frequently not effective. Recent epidemiological studies suggest that the anti-hyperglycemic agent metformin may reduce the risk of developing cancer, including ESCC, among diabetic patients. However, the antitumor effects of metformin on ESCC and the mechanisms underlying its cell cycle regulation remain elusive. The findings reported herein show that the anti-proliferative action of metformin on ESCC cell lines is partially mediated by AMPK. Moreover, we observed that metformin induced G0/G1 phase arrest accompanied by the up-regulation of p21CIP1 and p27KIP1. In vivo experiments further showed that metformin inhibited tumor growth in a ESCC xenograft model. Most importantly, the up-regulation of AMPK, p53, p21CIP1, p27KIP1 and the down-regulation of cyclinD1 are involved in the anti-tumor action of metformin in vivo. In conclusion, metformin inhibits the growth of ESCC cells both in cell cultures and in an animal model. AMPK, p53, p21CIP1, p27KIP1 and cyclinD1 are involved in the inhibition of tumor growth that is induced by metformin and cell cycle arrest in ESCC. These findings indicate that metformin has the potential for use in the treatment of ESCC.

No MeSH data available.


Related in: MedlinePlus