Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia.
Institute for Biological Research "Sinisa Stankovic", University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia.
Eur J Pharm Sci. 2019 Oct 1;138:105012. doi: 10.1016/j.ejps.2019.105012. Epub 2019 Jul 19.
New 6-triazolyl-substituted sulfocoumarins were described as potent inhibitors of the transmembrane human carbonic anhydrase isoforms, CAIX and CAXII. These membrane associated enzymes that maintain pH and CO homeostasis are involved in cancer progression, invasion, and resistance to therapy. Recently, it was shown that CAXII expression associates with the expression of P-glycoprotein in multidrug resistant cancer cells. CAXII regulates P-glycoprotein activity by maintaining high intracellular pHi. In this study, the activity of three new sulfocoumarins was evaluated in three sensitive and corresponding multidrug resistant cancer cell lines with increased P-glycoprotein expression (non-small cell lung carcinoma, colorectal carcinoma and glioblastoma). Compound 3 showed the highest potential for cancer cell growth inhibition in all tested cell lines. Flow cytometric analyses showed that compound 3 induced intracellular acidification, cell cycle arrest in G/M phase and necrosis in non-small cell lung carcinoma cells. Compound 3 demonstrated irreversible, concentration- and time-dependent inhibition of P-glycoprotein activity in multidrug resistant non-small cell lung carcinoma cells. The suppression of P-glycoprotein activity was accompanied with increased P-glycoprotein expression suggesting a compensatory mechanism of multidrug resistant cancer cells. In addition, compound 3 was able to sensitize multidrug resistant non-small cell lung carcinoma cells to doxorubicin. Overall, results imply that compound 3 has multidrug resistance modulating effect through intracellular acidification and subsequent inhibition of P-glycoprotein activity.
新型 6-三唑取代的磺酰基香豆素被描述为跨膜人碳酸酐酶同工型 CAIX 和 CAXII 的强效抑制剂。这些与膜相关的酶维持 pH 和 CO 平衡，参与癌症的进展、侵袭和对治疗的耐药性。最近表明，CAXII 的表达与多药耐药癌细胞中 P-糖蛋白的表达相关。CAXII 通过维持高细胞内 pHi 来调节 P-糖蛋白的活性。在这项研究中，三种新型磺酰基香豆素的活性在三种表达增加的多药耐药癌细胞系（非小细胞肺癌、结直肠癌和神经胶质瘤）中进行了评估。化合物 3 在所有测试的细胞系中表现出最强的抑制癌细胞生长的潜力。流式细胞术分析表明，化合物 3 诱导非小细胞肺癌细胞内酸化、G/M 期细胞周期停滞和坏死。化合物 3 在多药耐药非小细胞肺癌细胞中表现出不可逆、浓度和时间依赖性的 P-糖蛋白活性抑制。P-糖蛋白活性的抑制伴随着 P-糖蛋白表达的增加，表明多药耐药癌细胞存在代偿机制。此外，化合物 3 能够使多药耐药非小细胞肺癌细胞对阿霉素敏感。总的来说，结果表明，化合物 3 通过细胞内酸化和随后抑制 P-糖蛋白活性来调节多药耐药。
