Combined metformin and resveratrol confers protection against UVC-induced DNA damage in A549 lung cancer cells via modulation of cell cycle checkpoints and DNA repair.
Aging in humans is a multi-factorial cellular process that is associated with an increase in the risk of numerous diseases including diabetes, coronary heart disease and cancer. Aging is linked to DNA damage, and a persistent source of DNA damage is exposure to ultraviolet (UV) radiation. As such, identifying agents that confer protection against DNA damage is an approach that could reduce the public health burden of age-related disorders. Metformin and resveratrol have both shown effectiveness in preventing several age-related diseases; using human A549 cells, we investigated whether metformin or resveratrol, alone or combined, prevent UVC-induced DNA damage. We found that metformin inhibited UVC-induced upregulation of p53, as well as downregulated the expression of two DNA damage markers: γH2AX and p-chk2. Metformin also upregulated DNA repair as evidenced by the increase in expression of p53R2. Treatment with metformin also induced cell cycle arrest in UVC-induced cells, in correlation with a reduction in the levels of cyclin E/cdk2/Rb and cyclin B1/cdk1. Compared to metformin, resveratrol as a single agent showed less effectiveness in counteracting UVC-elicited cellular responses. However, resveratrol displayed synergism when combined with metformin as shown by the downregulation of p53/γH2AX/p-chk2. In conclusion, the results of the present study validate the effectiveness of metformin, alone or with the addition of resveratrol, in reducing the risk of aging by conferring protection against UV-induced DNA damage.
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Yong-Syu
YS
Lee
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Barbara B
BB
Doonan
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Joseph M
JM
Wu
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA.
Tze-Chen
TC
Hsieh
D000072283:A549 Cells; D000375:Aging / Q000187:drug effects*; D000972:Antineoplastic Agents, Phytogenic; D016203:CDC2 Protein Kinase; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects* / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D015513:Oncogene Proteins / Q000378:metabolism; D000077185:Resveratrol; D016160:Retinoblastoma Protein / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; C475820:CCNE1 protein, human; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D019927:Cyclin E; C468783:H2AX protein, human; D006657:Histones; D015513:Oncogene Proteins; D016160:Retinoblastoma Protein; D013267:Stilbenes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008687:Metformin; C405947:RRM2B protein, human; D012264:Ribonucleotide Reductases; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D000077185:Resveratrol