Xu Zhenyu, Chen Lu, Xiao Zhangang, Zhu Yanhong, Jiang Hui, Jin Yan, Gu Cheng, Wu Yilai, Wang Lin, Zhang Wen, Zuo Jian, Zhou Dexi, Luan Jiajie, Shen Jing
Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China.
Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China.
Phytomedicine. 2018 Dec 1;51:58-67. doi: 10.1016/j.phymed.2018.05.012. Epub 2018 May 19.
Gastric cancer is the fifth commonest cancer and the third cause of cancer-related deaths all over the world. The effectiveness of chemotherapy is still limited by drug resistance in gastric cancer. Tanshinones, abietane diterpenes isolated from the traditional Chinese medicine Danshen (Salvia miltiorrhiza), have exhibited versatile anticancer activities in particular the ability to overcome drug resistance in different cancers.
The current study aimed to explore the capacity of tanshinone IIA, the most abundant tanshinone found in the plant Danshen, to overcome drug resistance of gastric cancer cells to a commonly used anticancer drug doxorubicin.
Sensitivity of cell lines to doxorubicin was determined by MTT assay. Doxorubicin resistant gastric cancer cell lines was established by step selection with increasing concentrations of doxorubicin. Cell cycle arrest, apoptosis and doxorubicin efflux were analyzed by flow cytometry. The expression of MRP1 was determined by realtime PCR and western-blot.
Based on the IC values of doxorubicin, we identified the doxorubicin-sensitive gastric cancer cell lines SNU-719 and SNU-610 as well as the cell lines relatively resistant to doxorubicin including SNU-638, SNU-668, SNU-216 and SNU-620. We also established two drug-resistant cell lines SNU-719R and SNU-610R. Despite the fact that tanshinone IIA alone showed no cytotoxicity on these gastric cells, we found the potentiation of the anticancer effect of doxorubicin in drug-resistant gastric cancer cells by tanshinone IIA. Furthermore, using doxorubicin-sensitive cell line SNU-719 and doxorubicin-resistant cell lines SNU-719R and SNU-620, we revealed the pivotal roles of MRP1. Its overexpression impaired cell cycle arrest and suppressed apoptosis in the development of both intrinsic and acquired drug resistance in gastric cancer cells to doxorubicin. Importantly, inhibition of MRP1 function enhanced cell cycle arrest, increased apoptosis and induced autophagic cell death which contributed to the capability of tanshinone IIA to potentiate the anticancer effect of doxorubicin in drug-resistant gastric cancer cells.
Tanshinone IIA is an interesting agent with potential to treat drug-resistant gastric cancer in combination therapy.
胃癌是全球第五大常见癌症和癌症相关死亡的第三大原因。胃癌化疗的有效性仍然受到耐药性的限制。丹参酮是从传统中药丹参中分离出的松香烷二萜类化合物，在多种抗癌活性方面表现出色，尤其是在克服不同癌症的耐药性方面。
本研究旨在探讨丹参中含量最高的丹参酮IIA克服胃癌细胞对常用抗癌药物阿霉素耐药性的能力。
通过MTT法测定细胞系对阿霉素的敏感性。通过逐步增加阿霉素浓度进行筛选建立阿霉素耐药胃癌细胞系。通过流式细胞术分析细胞周期阻滞、凋亡和阿霉素外排。通过实时PCR和蛋白质免疫印迹法测定MRP1的表达。
根据阿霉素的IC值，我们鉴定出阿霉素敏感的胃癌细胞系SNU - 719和SNU - 610，以及对阿霉素相对耐药的细胞系，包括SNU - 638、SNU - 668、SNU - 216和SNU - 620。我们还建立了两个耐药细胞系SNU - 719R和SNU - 610R。尽管丹参酮IIA单独对这些胃癌细胞没有细胞毒性，但我们发现丹参酮IIA能增强阿霉素对耐药胃癌细胞的抗癌作用。此外，使用阿霉素敏感细胞系SNU - 719和阿霉素耐药细胞系SNU - 719R及SNU - 620，我们揭示了MRP1的关键作用。其过表达损害了细胞周期阻滞，并抑制了胃癌细胞对阿霉素的内在和获得性耐药发展过程中的凋亡。重要的是，抑制MRP1功能增强了细胞周期阻滞，增加了凋亡并诱导了自噬性细胞死亡，这有助于丹参酮IIA增强阿霉素对耐药胃癌细胞的抗癌作用。
丹参酮IIA是一种有潜力在联合治疗中治疗耐药胃癌的有趣药物。
