Liang Xin-Li, Ji Miao-Miao, Liao Zheng-Gen, Zhao Guo-Wei, Tang Xi-Lan, Dong Wei
Key Laboratory of Modern Preparation of Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Nanchang 330013, China.
Korean J Physiol Pharmacol. 2022 May 1;26(3):145-155. doi: 10.4196/kjpp.2022.26.3.145.
Multidrug resistance of tumors has been a severe obstacle to the success of cancer chemotherapy. The study wants to investigate the reversal effects of imperatorin (IMP) on doxorubicin (DOX) resistance in K562/DOX leukemia cells, A2780/Taxol cells and in NOD/SCID mice, to explore the possible molecular mechanisms. K562/DOX and A2780/Taxol cells were treated with various concentrations of DOX and Taol with or without different concentrations of IMP, respectively. K562/DOX xenograft model was used to assess anti-tumor effect of IMP combined with DOX. MTT assay, Rhodamine 123 efflux assay, RT-PCR, and Western blot analysis were determined and . Results showed that IMP significantly enhanced the cytotoxicity of DOX and Taxol toward corresponding resistance cells. In vivo results illustrated both the tumor volume and tumor weight were significantly decreased after 2-week treatment with IMP combined with DOX compared to the DOX alone group. Western blotting and RT-PCR analyses indicated that IMP downregulated the expression of P-gp in K562/DOX xenograft tumors in NOD/SCID mice. We also evaluated glycolysis and glutamine metabolism in K562/DOX cells by measuring glucose consumption and lactate production. The results revealed that IMP could significantly reduce the glucose consumption and lactate production of K562/DOX cells. Furthermore, IMP could also remarkably repress the glutamine consumption, α-KG and ATP production of K562/DOX cells. Thus, IMP may sensitize K562/DOX cells to DOX and enhance the anti-tumor effect of DOX in K562/DOX xenograft tumors in NOD/SCID mice. IMP may be an adjuvant therapy to mitigate the multidrug resistance in leukemia chemotherapy.
肿瘤的多药耐药性一直是癌症化疗成功的严重障碍。本研究旨在探讨欧前胡素（IMP）对K562/DOX白血病细胞、A2780/Taxol细胞以及NOD/SCID小鼠阿霉素（DOX）耐药性的逆转作用，以探索其可能的分子机制。分别用不同浓度的DOX和紫杉醇（Taol）处理K562/DOX和A2780/Taxol细胞，同时添加或不添加不同浓度的IMP。采用K562/DOX异种移植模型评估IMP联合DOX的抗肿瘤效果。进行MTT法、罗丹明123外排试验、RT-PCR和蛋白质免疫印迹分析。结果表明，IMP显著增强了DOX和紫杉醇对相应耐药细胞的细胞毒性。体内实验结果表明，与单独使用DOX组相比，IMP联合DOX治疗2周后，肿瘤体积和肿瘤重量均显著降低。蛋白质免疫印迹和RT-PCR分析表明，IMP下调了NOD/SCID小鼠K562/DOX异种移植瘤中P-糖蛋白的表达。我们还通过测量葡萄糖消耗和乳酸生成来评估K562/DOX细胞中的糖酵解和谷氨酰胺代谢。结果显示，IMP可显著降低K562/DOX细胞的葡萄糖消耗和乳酸生成。此外，IMP还可显著抑制K562/DOX细胞的谷氨酰胺消耗、α-酮戊二酸和ATP生成。因此，IMP可能使K562/DOX细胞对DOX敏感，并增强DOX在NOD/SCID小鼠K562/DOX异种移植瘤中的抗肿瘤作用。IMP可能是减轻白血病化疗中多药耐药性的辅助治疗药物。
