Department of Molecular Biology and Genetics, Faculty of Science and Letters, Ordu University, Ordu, Turkey.
Department of Urology, Cambridge Health Alliance, Cambridge, Massachusetts, USA.
Environ Mol Mutagen. 2021 Feb;62(2):143-154. doi: 10.1002/em.22424.
Pioglitazone (PIO), an oral hypoglycemic agent, is used in the treatment of type 2 diabetes. Some studies have suggested that an increased risk of bladder cancer with PIO exposure, while the others reported there is no such relationship. Therefore, it is doubtful whether PIO can increase the risk of bladder cancer. The effects of PIO on DNA damage and/or transformation of human bladder cells are not fully known. We investigated the effects of PIO on cytotoxicity, DNA single and double strand breaks and repair and neoplastic transformation in human bladder cells (hTU1) treated with 10, 20, and 40 μM PIO for 24, 48 and 72 hr. PIO decreased cell viability in a concentration-dependent manner. Increased levels of comet parameters showed that PIO and its metabolites can significantly induce DNA double strand breaks at all concentrations tested. PIO also significantly induced the formation of phosphorylated H2AX and p53 binding protein 1 foci. DNA damage was not repaired in a 24 hr recovery period. PIO can also induce malignant transformation of human bladder cells exhibiting loss of contact inhibition and anchorage independent growth. This is the first study to indicate that PIO can induce DNA damage and malignant transformation, reduce or alter the DNA repair capacity in human bladder cells. From these results, we suggest that patients with diabetes treated with PIO may have an increased risk of bladder cancer.
吡格列酮（PIO）是一种口服降糖药，用于治疗 2 型糖尿病。一些研究表明 PIO 暴露会增加膀胱癌的风险，而另一些研究则报告两者之间没有这种关系。因此，PIO 是否会增加膀胱癌的风险仍存在疑问。PIO 对人膀胱细胞 DNA 损伤和/或转化的影响尚不完全清楚。我们研究了 PIO 对人膀胱细胞（hTU1）的细胞毒性、DNA 单链和双链断裂以及修复和肿瘤转化的影响，细胞分别用 10、20 和 40μM PIO 处理 24、48 和 72 小时。PIO 呈浓度依赖性降低细胞活力。彗星参数水平的升高表明，PIO 及其代谢物可在所有测试浓度下显著诱导 DNA 双链断裂。PIO 还显著诱导磷酸化 H2AX 和 p53 结合蛋白 1 焦点的形成。在 24 小时的恢复期间，DNA 损伤未得到修复。PIO 还可以诱导人膀胱细胞的恶性转化，表现为丧失接触抑制和锚定非依赖性生长。这是第一项表明 PIO 可诱导 DNA 损伤和恶性转化、降低或改变人膀胱细胞 DNA 修复能力的研究。根据这些结果，我们建议接受 PIO 治疗的糖尿病患者膀胱癌风险可能增加。
