Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells.
Metformin is a biguanide drug that is widely used in the treatment of diabetes. Epidemiological studies have indicated that metformin exhibits anti-cancer activity. However, the molecular mechanisms underlying this activity currently remain unclear. We hypothesized that metformin is cytotoxic in a t...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5605006?pdf=render |
| _version_ | 1818585829678776320 |
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| author | Kei Kadoda Takahito Moriwaki Masataka Tsuda Hiroyuki Sasanuma Masamichi Ishiai Minoru Takata Hiroshi Ide Shin-Ichiro Masunaga Shunichi Takeda Keizo Tano |
| author_facet | Kei Kadoda Takahito Moriwaki Masataka Tsuda Hiroyuki Sasanuma Masamichi Ishiai Minoru Takata Hiroshi Ide Shin-Ichiro Masunaga Shunichi Takeda Keizo Tano |
| author_sort | Kei Kadoda |
| collection | DOAJ |
| description | Metformin is a biguanide drug that is widely used in the treatment of diabetes. Epidemiological studies have indicated that metformin exhibits anti-cancer activity. However, the molecular mechanisms underlying this activity currently remain unclear. We hypothesized that metformin is cytotoxic in a tumor-specific environment such as glucose deprivation and/or low oxygen (O2) tension. We herein demonstrated that metformin was highly cytotoxic under glucose-depleted, but not hypoxic (2% O2) conditions. In order to elucidate the underlying mechanisms of this selective cytotoxicity, we treated exposed DNA repair-deficient chicken DT40 cells with metformin under glucose-depleted conditions and measured cellular sensitivity. Under glucose-depleted conditions, metformin specifically killed fancc and fancl cells that were deficient in FANCC and FANCL proteins, respectively, which are involved in DNA interstrand cross-link repair. An analysis of chromosomal aberrations in mitotic chromosome spreads revealed that a clinically relevant concentration of metformin induced DNA double-strand breaks (DSBs) in fancc and fancl cells under glucose-depleted conditions. In summary, metformin induced DNA damage under glucose-depleted conditions and selectively killed cells. This metformin-mediated selective toxicity may suppress the growth of malignant tumors that are intrinsically deprived of glucose. |
| first_indexed | 2024-12-16T08:43:17Z |
| format | Article |
| id | doaj.art-ad7e64ff3a7e4adab1e9b9eca882b95a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-16T08:43:17Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-ad7e64ff3a7e4adab1e9b9eca882b95a2022-12-21T22:37:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01129e018514110.1371/journal.pone.0185141Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells.Kei KadodaTakahito MoriwakiMasataka TsudaHiroyuki SasanumaMasamichi IshiaiMinoru TakataHiroshi IdeShin-Ichiro MasunagaShunichi TakedaKeizo TanoMetformin is a biguanide drug that is widely used in the treatment of diabetes. Epidemiological studies have indicated that metformin exhibits anti-cancer activity. However, the molecular mechanisms underlying this activity currently remain unclear. We hypothesized that metformin is cytotoxic in a tumor-specific environment such as glucose deprivation and/or low oxygen (O2) tension. We herein demonstrated that metformin was highly cytotoxic under glucose-depleted, but not hypoxic (2% O2) conditions. In order to elucidate the underlying mechanisms of this selective cytotoxicity, we treated exposed DNA repair-deficient chicken DT40 cells with metformin under glucose-depleted conditions and measured cellular sensitivity. Under glucose-depleted conditions, metformin specifically killed fancc and fancl cells that were deficient in FANCC and FANCL proteins, respectively, which are involved in DNA interstrand cross-link repair. An analysis of chromosomal aberrations in mitotic chromosome spreads revealed that a clinically relevant concentration of metformin induced DNA double-strand breaks (DSBs) in fancc and fancl cells under glucose-depleted conditions. In summary, metformin induced DNA damage under glucose-depleted conditions and selectively killed cells. This metformin-mediated selective toxicity may suppress the growth of malignant tumors that are intrinsically deprived of glucose.http://europepmc.org/articles/PMC5605006?pdf=render |
| spellingShingle | Kei Kadoda Takahito Moriwaki Masataka Tsuda Hiroyuki Sasanuma Masamichi Ishiai Minoru Takata Hiroshi Ide Shin-Ichiro Masunaga Shunichi Takeda Keizo Tano Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells. PLoS ONE |
| title | Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells. |
| title_full | Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells. |
| title_fullStr | Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells. |
| title_full_unstemmed | Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells. |
| title_short | Selective cytotoxicity of the anti-diabetic drug, metformin, in glucose-deprived chicken DT40 cells. |
| title_sort | selective cytotoxicity of the anti diabetic drug metformin in glucose deprived chicken dt40 cells |
| url | http://europepmc.org/articles/PMC5605006?pdf=render |
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