Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo, 060-0812, Japan.
Department of Pharmacy, Hokkaido University Hospital, Kita-14-jo, Nishi-5-chome, Kita-ku, Sapporo, 060-8648, Japan.
Biochem Biophys Res Commun. 2020 Oct 1;530(4):745-750. doi: 10.1016/j.bbrc.2020.07.040. Epub 2020 Aug 8.
Cisplatin (CDDP) is a highly potent and important anticancer drug in lung cancer treatment. Long-term use of an anticancer agent causes resistance in cancer cells, and CDDP resistance involves multiple mechanisms. As the mechanism of resistance development differs depending on the cancer cell types, we aimed to evaluate the detailed mechanism of resistance to CDDP in two types of lung cancer cells: SBC-3 and A549 cells. The CDDP-resistant SBC-3/DDP and A549/DDP cells were established through continuous treatment with a gradually increasing dose of CDDP. The viability of SBC-3/DDP and A549/DDP cells treated with CDDP was 3.68 and 2.08 times higher than that of the respective parental cells. Moreover, SBC-3/DDP cells showed significantly increased cystine/glutamate transporter (xCT) mRNA level, and A549/DDP cells showed markedly increased sex determining region Y-box 2 (SOX2) mRNA level. Moreover, the uptake of cystine, a substrate of xCT, was higher in SBC-3/DDP cells than in SBC-3 cells, and cystine uptake in A549/DDP cells was not different from that in A549 cells. In addition, co-treatment with CDDP and sulfasalazine, an xCT inhibitor, showed lower the concentration of 50% inhibition for cell viability than CDDP alone in SBC-3 and SBC-3/DDP cells, but not in A549 and A549/DDP cells. Furthermore, SBC-3 cells transiently overexpressing xCT were resistant to CDDP, and xCT knockdown in A549/DDP cells did not significantly change the level of SOX2 mRNA and viability of cells upon CDDP treatment. In conclusion, the two lung cancer cell lines showed different mechanisms of resistance to CDDP.
顺铂（CDDP）是肺癌治疗中一种非常有效且重要的抗癌药物。长期使用抗癌药物会导致癌细胞产生耐药性，而 CDDP 耐药性涉及多种机制。由于耐药性发展的机制因癌细胞类型而异，我们旨在评估两种肺癌细胞系：SBC-3 和 A549 细胞中对 CDDP 耐药的详细机制。通过连续用逐渐增加剂量的 CDDP 处理，建立了耐药的 SBC-3/DDP 和 A549/DDP 细胞。用 CDDP 处理的 SBC-3/DDP 和 A549/DDP 细胞的活力分别比各自亲本细胞高 3.68 倍和 2.08 倍。此外，SBC-3/DDP 细胞显示出明显增加的胱氨酸/谷氨酸转运体（xCT）mRNA 水平，而 A549/DDP 细胞显示出明显增加的性别决定区 Y 框 2（SOX2）mRNA 水平。此外，SBC-3/DDP 细胞对胱氨酸的摄取量（xCT 的底物）高于 SBC-3 细胞，而 A549/DDP 细胞对胱氨酸的摄取量与 A549 细胞没有差异。此外，在用 CDDP 和柳氮磺胺吡啶（xCT 抑制剂）共同处理时，SBC-3 和 SBC-3/DDP 细胞的细胞活力 50%抑制浓度低于单独用 CDDP，而在 A549 和 A549/DDP 细胞中则没有。此外，瞬时过表达 xCT 的 SBC-3 细胞对 CDDP 具有耐药性，而在 A549/DDP 细胞中敲低 xCT 并没有显著改变 SOX2 mRNA 的水平和 CDDP 处理后细胞的活力。总之，这两种肺癌细胞系对 CDDP 的耐药机制不同。
