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Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells.

Lesan V, Ghaffari SH, Salaramoli J, Heidari M, Rostami M, Alimoghaddam K, Ghavamzadeh A - Int J Hematol Oncol Stem Cell Res (2014)

Bottom Line: The antagonistic effect of metformin on cisplatin could be through survivin and mTOR signaling pathways.Our results also suggest that interfering effect of metformin on cisplatin may be also through upregulation of Akt.Regarding the pivotal role of Akt in drug resistance, it may be reasonable to conclude that the antagonistic effect of metformin on cisplatin effect may be through this central mediator of drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran ; Department of Biology, Faculty of Food Industry and Agriculture, Standard Research Institute (SRI), Karaj, Iran.

ABSTRACT
Metformin has recently been introduced as an anti-cancer agent. In this study, we evaluated the effect of metformin and metformin/cisplatin on human gastric MKN-45 cell line. When we used metformin alone, it could inhibit proliferation and induce apoptosis, but it diminish anti-proliferative effects of cisplatin when they are used in combination. Further, we checked mRNA levels of survivin, mTOR, and Akt by real-time PCR. When MKN-45 cells were treated with metformin/cisplatin, the expression of survivin and mTOR were increased. The antagonistic effect of metformin on cisplatin could be through survivin and mTOR signaling pathways. Our results also suggest that interfering effect of metformin on cisplatin may be also through upregulation of Akt. Regarding the pivotal role of Akt in drug resistance, it may be reasonable to conclude that the antagonistic effect of metformin on cisplatin effect may be through this central mediator of drug resistance. Taken together, it seems that metformin is not a good option for sensitizing MKN-45 cell line to cisplatin, and in co-prescription of metformin and cisplatin in gastric cancer patients who suffer diabetes type 2, it should be highly cared.

No MeSH data available.


Related in: MedlinePlus

Effect of metformin, cisplatin and metformin/cisplatin on apoptosis in MKN-45 cells. A) Hoechst 33342 stains the condensed chromatin in apoptotic cells more brightly than the chromatin in normal cells and Propidium Iodide (PI) is only permeate to dead cells (FL2: PI, FL6: Hoechst 33342). As shown in figure, there is significant change in the apoptosis rate of metformin, cisplatin and metformin/cisplatin treated MKN-45 cells compared with the control. B) Quantified values of apoptosis in MKN-45 cell line treated with metformin, cisplatin and metformin/cisplatin. As shown in this figure, the cisplatin-induced apoptosis at concentration of 5 μM is significantly higher than the combination of metformin 10 /cisplatin 5. Statistically different values of *P<0.05 and **P<0.01 are determined compared with the control
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Figure 2: Effect of metformin, cisplatin and metformin/cisplatin on apoptosis in MKN-45 cells. A) Hoechst 33342 stains the condensed chromatin in apoptotic cells more brightly than the chromatin in normal cells and Propidium Iodide (PI) is only permeate to dead cells (FL2: PI, FL6: Hoechst 33342). As shown in figure, there is significant change in the apoptosis rate of metformin, cisplatin and metformin/cisplatin treated MKN-45 cells compared with the control. B) Quantified values of apoptosis in MKN-45 cell line treated with metformin, cisplatin and metformin/cisplatin. As shown in this figure, the cisplatin-induced apoptosis at concentration of 5 μM is significantly higher than the combination of metformin 10 /cisplatin 5. Statistically different values of *P<0.05 and **P<0.01 are determined compared with the control

Mentions: To evaluate the effects of metformin, cisplatin and metformin/cisplatin on apoptosis in MKN-45 cell line, we used flow cytometry. As shown in Fig. 2, the analyzed data obtained from FlowMax software revealed that cisplatin could induce higher apoptosis compared to the untreated control either in concentration 1 μM (P<0.05) or 5 and 10 μM (P<0.01). However, the apoptosis ratio was reduced in the combination treatments as compared to the cisplatin alone. The induction of apoptosis in combination of metformin 10/cisplatin 5 was significantly lower than cisplatin alone at concentration of 5 μM (P<0.05). This data indicate that metformin antagonizes with cisplatin-induced apoptosis.


Evaluation of antagonistic effects of metformin with Cisplatin in gastric cancer cells.

Lesan V, Ghaffari SH, Salaramoli J, Heidari M, Rostami M, Alimoghaddam K, Ghavamzadeh A - Int J Hematol Oncol Stem Cell Res (2014)

Effect of metformin, cisplatin and metformin/cisplatin on apoptosis in MKN-45 cells. A) Hoechst 33342 stains the condensed chromatin in apoptotic cells more brightly than the chromatin in normal cells and Propidium Iodide (PI) is only permeate to dead cells (FL2: PI, FL6: Hoechst 33342). As shown in figure, there is significant change in the apoptosis rate of metformin, cisplatin and metformin/cisplatin treated MKN-45 cells compared with the control. B) Quantified values of apoptosis in MKN-45 cell line treated with metformin, cisplatin and metformin/cisplatin. As shown in this figure, the cisplatin-induced apoptosis at concentration of 5 μM is significantly higher than the combination of metformin 10 /cisplatin 5. Statistically different values of *P<0.05 and **P<0.01 are determined compared with the control
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4305376&req=5

Figure 2: Effect of metformin, cisplatin and metformin/cisplatin on apoptosis in MKN-45 cells. A) Hoechst 33342 stains the condensed chromatin in apoptotic cells more brightly than the chromatin in normal cells and Propidium Iodide (PI) is only permeate to dead cells (FL2: PI, FL6: Hoechst 33342). As shown in figure, there is significant change in the apoptosis rate of metformin, cisplatin and metformin/cisplatin treated MKN-45 cells compared with the control. B) Quantified values of apoptosis in MKN-45 cell line treated with metformin, cisplatin and metformin/cisplatin. As shown in this figure, the cisplatin-induced apoptosis at concentration of 5 μM is significantly higher than the combination of metformin 10 /cisplatin 5. Statistically different values of *P<0.05 and **P<0.01 are determined compared with the control
Mentions: To evaluate the effects of metformin, cisplatin and metformin/cisplatin on apoptosis in MKN-45 cell line, we used flow cytometry. As shown in Fig. 2, the analyzed data obtained from FlowMax software revealed that cisplatin could induce higher apoptosis compared to the untreated control either in concentration 1 μM (P<0.05) or 5 and 10 μM (P<0.01). However, the apoptosis ratio was reduced in the combination treatments as compared to the cisplatin alone. The induction of apoptosis in combination of metformin 10/cisplatin 5 was significantly lower than cisplatin alone at concentration of 5 μM (P<0.05). This data indicate that metformin antagonizes with cisplatin-induced apoptosis.

Bottom Line: The antagonistic effect of metformin on cisplatin could be through survivin and mTOR signaling pathways.Our results also suggest that interfering effect of metformin on cisplatin may be also through upregulation of Akt.Regarding the pivotal role of Akt in drug resistance, it may be reasonable to conclude that the antagonistic effect of metformin on cisplatin effect may be through this central mediator of drug resistance.

View Article: PubMed Central - PubMed

Affiliation: Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran ; Department of Biology, Faculty of Food Industry and Agriculture, Standard Research Institute (SRI), Karaj, Iran.

ABSTRACT
Metformin has recently been introduced as an anti-cancer agent. In this study, we evaluated the effect of metformin and metformin/cisplatin on human gastric MKN-45 cell line. When we used metformin alone, it could inhibit proliferation and induce apoptosis, but it diminish anti-proliferative effects of cisplatin when they are used in combination. Further, we checked mRNA levels of survivin, mTOR, and Akt by real-time PCR. When MKN-45 cells were treated with metformin/cisplatin, the expression of survivin and mTOR were increased. The antagonistic effect of metformin on cisplatin could be through survivin and mTOR signaling pathways. Our results also suggest that interfering effect of metformin on cisplatin may be also through upregulation of Akt. Regarding the pivotal role of Akt in drug resistance, it may be reasonable to conclude that the antagonistic effect of metformin on cisplatin effect may be through this central mediator of drug resistance. Taken together, it seems that metformin is not a good option for sensitizing MKN-45 cell line to cisplatin, and in co-prescription of metformin and cisplatin in gastric cancer patients who suffer diabetes type 2, it should be highly cared.

No MeSH data available.


Related in: MedlinePlus