Zhenyu Xu1, Lu Chen1, Zhangang Xiao2, Yanhong Zhu1, Hui Jiang1, Yan Jin3, Cheng Gu1, Yilai Wu1, Lin Wang1, Wen Zhang1, Jian Zuo1, Dexi Zhou1, Jiajie Luan4, Jing Shen5. 1. Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China. 2. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. 3. Department of Gastrointestinal Surgery, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China. 4. Department of Pharmacy, Yijishan Affiliated Hospital of Wannan Medical College, Wuhu, Anhui Province, China. Electronic address: luanjiajie757@163.com. 5. Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, China. Electronic address: crystal_stray@126.com.
Abstract
BACKGROUND: 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. PURPOSE: 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. STUDY DESIGN: 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. RESULTS: Based on the IC50 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. CONCLUSION: Tanshinone IIA is an interesting agent with potential to treat drug-resistant gastric cancer in combination therapy.
BACKGROUND: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, abietanediterpenes 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. PURPOSE: 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. STUDY DESIGN: 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. RESULTS: Based on the IC50 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. CONCLUSION:Tanshinone IIA is an interesting agent with potential to treat drug-resistant gastric cancer in combination therapy.
Authors: Huan Zhao; Bing Han; Xuan Li; Chengtao Sun; Yufei Zhai; Man Li; Mi Jiang; Weiping Zhang; Yi Liang; Guoyin Kai Journal: Front Pharmacol Date: 2022-05-05 Impact factor: 5.988