Dapagliflozin, empagliflozin, tofogliflozin, selective inhibitors of sodium-glucose cotransporter 2 (SGLT2), is used clinically to reduce circulation glucose levels in patients with type 2 diabetes mellitus by blocking the reabsorption of glucose by the kidneys. Dapagliflozin is metabolized and inactivated by UGT1A9. Empagliflozin is metabolized and inactivated by UGT1A9 and by other related isoforms UGT2B7, UGT1A3, and UGT1A8. Tofogliflozin is metabolized and inactivated by five different enzymes CYP2C18, CYP3A4, CYP3A5, CYP4A11, and CYP4F3. Dapagliflozin treatment of HCT116 cells, which express SGLT2 but not UGT1A9, results in the loss of cell adhesion, whereas HepG2 cells, which express both SGLT2 and UGT1A9, are resistant to the adhesion-related effects of dapagliflozin. PANC-1 and H1792 cells, which do not express either SGLT2 or UGT1A9, are also resistant to adhesion related effects of dapagliflozin. On the other hand, either empagliflozin or tofogliflozin treatment of HCT116, HepG2, PANC-1, and H1792 cells are resistant to the adhesion-related effects as observed in dapagliflozin treated HCT116 cells. Knockdown of UGT1A9 by shRNA in HepG2 cells increased dapagliflozin sensitivity, whereas the overexpression of UGT1A9 in HCT116 cells protected against dapagliflozin-dependent loos of cell adhesion. Dapagliflozin treatment had no effect on cellular interactions with fibronectin, vitronectin, or laminin, but it induced a loss of interaction with collagen I and IV. In parallel, dapagliflozin treatment reduced protein levels of the full-length discoidin domain receptor I (DDR1), concomitant with appearance of DDR1 cleavage products and ectodomain shedding of DDR1. In line with these observations, unmetabolized dapagliflozin increased ADAM10 activity. Dapagliflozin treatment also significantly reduced Y792 tyrosine phosphorylation of DDR1 leading to decrement of DDR1 function and detachment of cancer cells. Concomitant with these lines of results, we experienced that CEA in patients with colon cancer, which express SGLT2 but not UGT1A9, and type 2 diabetes mellitus treated by dapagliflozin in addition to chemotherapy was decreased (case 1). CEA in patients with colon cancer, which express SGLT2 but not UGT1A9, and type 2 diabetes mellitus was treated by dapagliflozin alone after radiation therapy was decreased but started to rise after cessation of dapagliflozin (case 2). CA19-9 in two of patients with pancreatic cancer and type 2 diabetes mellitus was resistant to the combination therapy of dapagliflozin and chemotherapy (case 3 and 4 respectively). PIVKAII in patients with liver cancer and type 2 diabetes mellitus, and CYFRA in patients with squamous lung cancer and type 2 diabetes mellitus was also resistant the combination therapy of dapagliflozin and chemotherapy (case 5 and 6 respectively). Taken together, these data suggest a potential role for dapagliflozin anticancer therapy against colon cancer cells that express SGLT2, but not UGT1A9.

中文翻译：

---

Dapagliflozin 通过增加 ADAM10 活性抑制细胞对胶原蛋白 I 和 IV 的粘附并增加 DDR1 的胞外域蛋白水解裂解

Dapagliflozin、empagliflozin、tofogliflozin 是钠-葡萄糖协同转运蛋白 2 (SGLT2) 的选择性抑制剂，临床上用于通过阻断肾脏对葡萄糖的重吸收来降低 2 型糖尿病患者的循环葡萄糖水平。Dapagliflozin 被 UGT1A9 代谢和灭活。Empagliflozin 被 UGT1A9 和其他相关同种型 UGT2B7、UGT1A3 和 UGT1A8 代谢和灭活。Tofogliflozin 被五种不同的酶 CYP2C18、CYP3A4、CYP3A5、CYP4A11 和 CYP4F3 代谢和灭活。Dapagliflozin 处理表达 SGLT2 但不表达 UGT1A9 的 HCT116 细胞导致细胞粘附丧失，而同时表达 SGLT2 和 UGT1A9 的 HepG2 细胞对达格列净的粘附相关作用具有抗性。不表达 SGLT2 或 UGT1A9 的 PANC-1 和 H1792 细胞，也抵抗达格列净的粘附相关作用。另一方面，如在 dapagliflozin 处理的 HCT116 细胞中观察到的，empagliflozin 或 tofogliflozin 处理的 HCT116、HepG2、PANC-1 和 H1792 细胞对粘附相关作用具有抗性。HepG2 细胞中 shRNA 对 UGT1A9 的敲低增加了达格列净敏感性，而 HCT116 细胞中 UGT1A9 的过表达可防止达格列净依赖的细胞粘附丧失。Dapagliflozin 处理对细胞与纤连蛋白、玻连蛋白或层粘连蛋白的相互作用没有影响，但会导致与胶原蛋白 I 和 IV 的相互作用丧失。与此同时，dapagliflozin 治疗降低了全长盘状结构域受体 I (DDR1) 的蛋白质水平，伴随着 DDR1 切割产物的出现和 DDR1 的胞外域脱落。与这些观察结果一致，未代谢的达格列净增加了 ADAM10 的活性。Dapagliflozin 治疗还显着降低了 DDR1 的 Y792 酪氨酸磷酸化，导致 DDR1 功能下降和癌细胞脱离。伴随这些结果，我们发现表达 SGLT2 但不表达 UGT1A9 的结肠癌患者和 2 型糖尿病患者的 CEA 减少，同时接受达格列净联合化疗（病例 1）。表达 SGLT2 但不表达 UGT1A9 的结肠癌和 2 型糖尿病患者的 CEA 在放射治疗后仅用达格列净治疗减少，但在停止达格列净后开始升高（病例 2）。两名胰腺癌和 2 型糖尿病患者的 CA19-9 对达格列净和化疗的联合治疗耐药（分别为病例 3 和 4）。肝癌和2型糖尿病患者的PIVKAII和鳞状肺癌和2型糖尿病患者的CYFRA也对达格列净联合化疗耐药（分别为病例5和6）。总之，这些数据表明达格列净对表达 SGLT2 但不表达 UGT1A9 的结肠癌细胞的抗癌治疗具有潜在作用。CYFRA 和 CYFRA 在鳞状肺癌和 2 型糖尿病患者中也对达格列净联合化疗耐药（分别为病例 5 和 6）。总之，这些数据表明达格列净对表达 SGLT2 但不表达 UGT1A9 的结肠癌细胞的抗癌治疗具有潜在作用。CYFRA 和 CYFRA 在鳞状肺癌和 2 型糖尿病患者中也对达格列净联合化疗耐药（分别为病例 5 和 6）。总之，这些数据表明达格列净对表达 SGLT2 但不表达 UGT1A9 的结肠癌细胞的抗癌治疗具有潜在作用。