探索钠-葡萄糖共转运蛋白作为癌症治疗新靶点的作用。
Exploring the Role of Sodium-Glucose Cotransporter as a New Target for Cancer Therapy.
机构信息
Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman, Jordan.
出版信息
J Pharm Pharm Sci. 2022;25:253-265. doi: 10.18433/jpps32879.
PURPOSE
To evaluate the effects of SGLT2 inhibitors on the proliferation, tumorigenesis, migration, colony formation, apoptosis, selected gene expression pattern, and combination with known chemotherapeutic drugs in different human cancer cell lines.
METHODS
The antiproliferative and combined effects of SGLT2 inhibitors were evaluated by MTT assay. Cell migration was assessed using wound-healing and colony formation assays. Apoptosis assay was conducted using annexin V-FITC/ propidium iodide staining. SGLT2 gene expression was determined using real-time PCR.
RESULTS
Canagliflozin, dapagliflozin, and ipragliflozin significantly inhibited the growth of different cancer cell lines in a dose and time-dependent manner. IC50 values after 48 hours of treatment with canagliflozin, ipragliflozin, and dapagliflozin ranged from 41.97 µM to 69.49 µM, 63.67 µM to 255.80 µM, and 167.7 µM to 435.70 µM in the examined cancer cell lines, respectively. The combined treatment of SGLT2 with doxorubicin and raloxifene separately resulted in a synergistic effect in Caco-2 and A-549 cell lines. On the other hand, the combination of SGLT2 inhibitors with cisplatin resulted in an antagonistic effect in A-549, Du-145, and Panc-1 cell lines. Canagliflozin and ipragliflozin inhibited cell migration and colony formation ability at IC50 and Sub-IC50 in the examined cancer cell lines. Canagliflozin and ipragliflozin significantly induced apoptosis at IC50 and Double-IC50 in the Du-145 cell line compared to the control. Real-time PCR showed that the treatment with 0.1 IC50 and 0.2 IC50 of both canagliflozin and ipragliflozin resulted in diminished RNA expression of SGLT2, VEGF, and Bcl-2 genes in the Du-145 cell line.
CONCLUSION
SGLT2 inhibitors have antiproliferation, anti-tumorigenesis, and anti-migration effects and may induce apoptosis in cancer cells. In addition, treatment with SGLT2 inhibitors resulted in the downregulation of selected genes in the Du-145 cell line.
目的
评估 SGLT2 抑制剂对不同人源癌细胞系增殖、致瘤性、迁移、集落形成、凋亡、特定基因表达模式的影响，并评估其与已知化疗药物的联合作用。
方法
通过 MTT 法评估 SGLT2 抑制剂的抗增殖和联合作用。使用划痕愈合和集落形成实验评估细胞迁移。通过 Annexin V-FITC/PI 染色进行凋亡实验。使用实时 PCR 测定 SGLT2 基因表达。
结果
坎格列净、达格列净和依帕列净以剂量和时间依赖性方式显著抑制不同癌细胞系的生长。在检测的癌细胞系中，坎格列净、依帕列净和达格列净在 48 小时治疗后的 IC50 值分别为 41.97µM 至 69.49µM、63.67µM 至 255.80µM 和 167.7µM 至 435.70µM。SGLT2 与阿霉素和雷洛昔芬分别联合治疗在 Caco-2 和 A-549 细胞系中产生协同作用。另一方面，SGLT2 抑制剂与顺铂联合治疗在 A-549、Du-145 和 Panc-1 细胞系中产生拮抗作用。坎格列净和依帕列净在检测的癌细胞系中以 IC50 和亚 IC50 抑制细胞迁移和集落形成能力。坎格列净和依帕列净在 Du-145 细胞系中以 IC50 和双 IC50 显著诱导凋亡，与对照组相比。实时 PCR 显示，在 Du-145 细胞系中，用 0.1 IC50 和 0.2 IC50 的坎格列净和依帕列净处理可导致 SGLT2、VEGF 和 Bcl-2 基因的 RNA 表达降低。
结论
SGLT2 抑制剂具有抗增殖、抗肿瘤生成和抗迁移作用，并可诱导癌细胞凋亡。此外，SGLT2 抑制剂的治疗导致 Du-145 细胞系中选定基因的下调。
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