| Cellular study |
1. Hyperglycemia induces epithelial-mesenchymal transition [94]. |
| 2. Metformin inhibits PCa cell proliferation, migration, and progression [68,95,97,98,99]. |
| 3. Metformin sensitizes PCa cells to radiation [115]. |
| 4. Metformin’s anti-neoplastic activity can be enhanced by the combination use with rapamycin [95], 2-deoxyglucose [105], simvastatin [106,107], doxorubicin [108], an inhibitor of polo-like kinase 1 [109], an inhibitor of enhancer of zeste homolog 2 [100], valproic acid [110], exendin 4 [111], aspirin [112], or solamargine [113]. |
| 5. Metformin in combination with abiraterone or enzalutamide enhances apoptosis in PCa cell lines [114]. |
| Animal studies |
1. Administration of metformin to mice bearing xenografts of human PCa cell line (LNCaP) results in a reduction of tumor growth by 35% to 50% [96]. |
| 2. Metformin postpones high-fat diet induced PCa in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice [116] |
| 3. Anti-tumor effect of metformin on PCa in immunosuppressed mice is more promient if the animals are fed a high-fat diet [69]. |
| 4. Metformin attenuates the development of prostate intraepithelial neoplasia by suppressing the oncogen c-myc [101]. |
| 5. Metformin sensitizes PCa cells to radiation [115]. |
| 6. Metformin reduced metastasis of PCa in nude mice [117]. |
| Human studies |
1. Metformin use is associated with a lower risk of PCa in patients with type 2 diabetes mellitus [126,127,128]. |
| 2. Meta-analyses do not consistently conclude with a reduced risk of PCa associated with metformin use. Refer to metaanalyses by Yu et al [129] and Wang et al [130]. |
| 3. The reduced risk of PCa associated with metformin use is especially significant when it is used with statin [134,135] or finasteride [135]. |
| 4. The association between metformin use and PCa aggressiveness can be modified by race [135,136]. |
| 5. Metformin use as an adjuvant therapy for PCa is under investigation, but the prognosis of PCa associated with metformin use is not conclusive. For some meta-analyses, please refer to: [129,141,142,143,145]. |
| Author’s comments |
1. Whether metformin may affect the risk of PCa in diabetes patients or affect the prognosis of patients with PCa is not conclusive. |
| 2. Metformin is currently being investigated as an adjuvant therapy for PCa in more than 26 clinical trials [20]. |
| 3. Intestersted readers may refer to review articles by Wang and Olumi [84], Zaidi et al [102], Hayashi et al [103], Hatano et al [104], and Campi et al [144]. |
