Multidrug resistance (MDR) that occurs in cancer cells constitutes one of the major reasons for chemotherapy failure. The main molecular mechanism of MDR is overexpression of protein transporters from the ATP-binding cassette (ABC) superfamily, such as ABCB1 (multidrug resistance protein 1 (MDR1), P-glycoprotein). At the expense of ATP hydrolysis, ABCB1 pumps a diverse range of substrates (including anticancer drugs) out of the cell, thereby reducing their intracellular concentration. In the present study, the ability of two patented disiloxanes (SILA-409 and SILA-421) to reverse drug resistance in human colon adenocarcinoma cell lines LoVo and LoVo/Dx was investigated. It was demonstrated that both compounds in concentrations of 0.5–1 µM strongly increased the sensitivity of LoVo/Dx cells to doxorubicin. By means of an accumulation test in which rhodamine 123 was used as an ABCB1 substrate analogue, both organosilicon compounds were also shown to inhibit ABCB1 transport activity. The intracellular accumulation of doxorubicin was also increased, and more drug entered the cellular nuclei of resistant cells in the presence of the studied compounds. In conclusion, both SILA-409 and SILA-421 were demonstrated to be effective MDR reversal agents in resistant human colon cancer cells.

中文翻译：

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有机硅化合物 SILA-409 和 SILA-421，作为人结肠癌细胞中阿霉素抗性逆转剂

癌细胞中发生的多药耐药（MDR）是化疗失败的主要原因之一。MDR 的主要分子机制是来自 ATP 结合盒 (ABC) 超家族的蛋白质转运蛋白的过度表达，例如 ABCB1（多药耐药蛋白 1 (MDR1)，P-糖蛋白）。以 ATP 水解为代价，ABCB1 将多种底物（包括抗癌药物）泵出细胞，从而降低它们的细胞内浓度。在本研究中，研究了两种获得专利的二硅氧烷（SILA-409 和 SILA-421）逆转人结肠腺癌细胞系 LoVo 和 LoVo/Dx 耐药性的能力。结果表明，浓度为 0.5–1 µM 的两种化合物均显着提高了 LoVo/Dx 细胞对阿霉素的敏感性。通过使用罗丹明 123 作为 ABCB1 底物类似物的累积试验，两种有机硅化合物也显示出抑制 ABCB1 转运活性。阿霉素的细胞内积累也增加了，并且在所研究的化合物存在的情况下，更多的药物进入了抗性细胞的细胞核。总之，SILA-409 和 SILA-421 都被证明是抗性人结肠癌细胞中有效的 MDR 逆转剂。