药学学报, 2018, 53(9): 1511-1517
引用本文:
韩立, 郭晓娟, 陈重, 卞华, 张超云, 臧文华, 王倩, 胡久略. 丹皮酚逆转卵巢癌SKOV3/DDP细胞多药耐药性的机制[J]. 药学学报, 2018, 53(9): 1511-1517.
HAN Li, GUO Xiao-juan, CHEN Zhong, BIAN Hua, ZHANG Chao-yun, ZANG Wen-hua, WANG Qian, HU Jiu-lue. The mechanisms of paeonol reversing multidrug resistance in ovarian cancer SKOV3/DDP cells[J]. Acta Pharmaceutica Sinica, 2018, 53(9): 1511-1517.

丹皮酚逆转卵巢癌SKOV3/DDP细胞多药耐药性的机制
韩立1,2, 郭晓娟1,2, 陈重3, 卞华1,2, 张超云1,2, 臧文华1,2, 王倩1,2, 胡久略1,2
1. 南阳理工学院 张仲景国医国药学院, 河南 南阳 473004;
2. 南阳理工学院 河南省张仲景方药与免疫调节重点实验室, 河南 南阳 473004;
3. 苏州大学药学院, 江苏 苏州 215123
摘要:
本文在卵巢癌耐药性SKOV3/DDP细胞中,检测丹皮酚(paeonol,PL)逆转卵巢癌耐药的作用,探讨其逆转耐药的机制。结果显示,PL对SKOV3/DDP细胞具有耐药逆转作用。流式细胞术检测发现,PL可浓度依赖性地抑制P糖蛋白(P-glycoprotein,P-gp)功能;采用荧光定量PCR和细胞免疫荧光技术,检测发现15、30和60 μmol·L-1 PL对MDR1/P-gp和异黏蛋白(metadherin,MTDH)的抑制作用,及对磷酸酶和张力蛋白类似物(phosphatase and tensin homolog,PTEN)的诱导作用均逐渐增强(P < 0.01,P < 0.05)。PI3K抑制剂LY294002对PTEN mRNA的诱导和MTDH mRNA的抑制作用均强于或相当于60 μmol·L-1 PL组,但其诱导PTEN蛋白和抑制MTDH蛋白的作用仅与15 μmol·L-1 PL组相当。本研究表明,PL对SKOV3/DDP细胞的逆转耐药作用可能与抑制P-gp功能和MDR1/P-gp、MTDH表达,诱导PTEN表达有关,为PL作为耐药逆转剂应用于卵巢癌耐药治疗提供了理论依据。
关键词:    丹皮酚      卵巢癌      多药耐药      异黏蛋白      磷酸酶和张力蛋白类似物     
The mechanisms of paeonol reversing multidrug resistance in ovarian cancer SKOV3/DDP cells
HAN Li1,2, GUO Xiao-juan1,2, CHEN Zhong3, BIAN Hua1,2, ZHANG Chao-yun1,2, ZANG Wen-hua1,2, WANG Qian1,2, HU Jiu-lue1,2
1. Zhang Zhongjing College of Chinese Medicine, Nanyang Institute of Technology, Nanyang 473004, China;
2. Henan Key Laboratory of Zhang Zhongjing Formulae and Herbs for Immunoregulation, Nanyang Institute of Technology, Nanyang 473004, China;
3. College of Pharmaceutical Science, Soochow University, Suzhou 215123, China
Abstract:
The purpose of this research is to investigate the effects and mechanisms of paeonol (PL), a phenolic compound found in many traditional Chinese formulations, on reversing drug resistance in the ovarian cancer resistant SKOV3/DDP cells. The results showed that PL had significant drug-resistant reversal effect on SKOV3/DDP cells. Flow cytometry showed that PL could inhibit P-glycoprotein (P-gp) function in a concentration-dependent manner. Fluorescent quantitative PCR and cell immunofluorescence techniques were used to detect mechanisms of action. Results revealed that both the inhibitory effect on MDR1/P-gp and metadherin (MTDH) expression and the induction effect on phosphatase and tensin homolog (PTEN), by 15, 30, and 60 μmol·L-1 PL, were increased with increased concentrations of PL (P < 0.01, P < 0.05). The inhibitory effect on MTDH mRNA and the induction effect on PTEN mRNA, by PI3K inhibitor LY294002, were stronger or equivalent to that of the 60 μmol·L-1 PL treated group; however, the inhibition or induction effect on MTDH or PTEN protein were only comparable to the 15 μmol·L-1 PL treated group. The present study shows that the effect of PL on SKOV3/DDP cells may be related to the inhibition of P-gp function and expression, the inhibition of MDR1, MTDH expression, and the induction of PTEN expression, all which can provide a theoretical foundation for PL as a drug resistance reversal agent on the treatment of ovarian cancer chemotherapy resistance.
Key words:    paeonol    ovarian cancer    multidrug resistance    metadherin    phosphatase and tensin homolog   
收稿日期: 2018-05-02
DOI: 10.16438/j.0513-4870.2018-0407
基金项目: 河南省自然科学基金资助项目(162300410204).
通讯作者: 韩立,Tel:86-377-62071309,E-mail:hanlee@live.cn;卞华,Tel:86-377-62071311,E-mail:biancrown@163.com
Email: hanlee@live.cn;biancrown@163.com
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参考文献:
[1] Allemani C, Matsuda T, di Carlo V, et al. Global surveillance of trends in cancer survival 2000-14(CONCORD-3):analysis of individual records for 37513025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries[J]. Lancet, 2018, 391:1023-1075.
[2] NCCN Guidelines Version 5. 2017:Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer & less common histopathologies[EB/OL]. Washington:National Comprehensive Cancer Network, 2018[2018-02-02]. https://www.nccn.org/professionals/physician_gls/pdf/ovarian.pdf.
[3] Sarkar D, Fisher PB. AEG-1/MTDH/LYRIC:Clinical Significance[M]. Oxford:Academic Press, 2013:39-74.
[4] Zhu GC, Yu CY, She L, et al. Metadherin regulation of vascular endothelial growth factor expression is dependent upon the PI3K/AKT pathway in squamous cell carcinoma of the head and neck[J]. Medicine (Baltimore), 2015, 94:e502.
[5] Burris HA. Overcoming acquired resistance to anticancer therapy:focus on the PI3K/AKT/mTOR pathway[J]. Cancer Chemother Pharmacol, 2013, 71:829-842.
[6] Du C, Yi X, Liu W, et al. MTDH mediates trastuzumab resistance in HER2 positive breast cancer by decreasing PTEN expression through an NFκB-dependent pathway[J]. BMC Cancer, 2014, 14:869.
[7] Weberpals JI, Amin MS, Chen BE, et al. First application of the automated quantitative analysis (AQUA) technique to quantify PTEN protein expression in ovarian cancer:a correlative study of NCIC CTG OV.16[J]. Gynecol Oncol, 2016, 140:486-493.
[8] Wang L, Wang C, Jin S, et al. Expression of NF-κB and PTEN in primary epithelial ovarian carcinoma and the correlation with chemoresistance[J]. Int J Clin Exp Pathol, 2015, 8:10953-10963.
[9] Zhang L, Tao L, Shi T, et al. Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-κB and STAT3 pathways[J]. IUBMB Life, 2015, 67:778-788.
[10] Li QN, Wang LL, Tang JM, et al. Anticancer activity of paeonol on human ovarian cancer A2780 cells by inhibiting Wnt/β-catenin signal pathway[J]. J Chin Pract Diagn Ther, 2017, 31:1062-1066.
[11] Wang YH, Imai Y, Shiseki M, et al. Knockdown of the Wnt receptor Frizzled-1(FZD1) reduces MDR1/P-glycoprotein expression in multidrug resistant leukemic cells and inhibits leukemic cell proliferation[J]. Leuk Res, 2018, 67:99-108.
[12] Cai J, Chen S, Zhang W, et al. Paeonol reverses paclitaxel resistance in human breast cancer cells by regulating the expression of transgelin 2[J]. Phytomedicine, 2014, 21:984-991.
[13] Xu L, Cai J, Yang Q, et al. Prognostic significance of several biomarkers in epithelial ovarian cancer:a meta-analysis of published studies[J]. J Cancer Res Clin Oncol, 2013, 139:1257-1277.
[14] Li C, Li Y, Wang X, et al. Elevated expression of astrocyte elevated gene-1(AEG-1) is correlated with cisplatin-based chemoresistance and shortened outcome in patients with stages Ⅲ-IV serous ovarian carcinoma[J]. Histopathology, 2012, 60:953-963.
[15] Wei YB, Guo Q, Gao YL, et al. Repression of metadherin inhibits biological behavior of prostate cancer cells and enhances their sensitivity to cisplatin[J]. Mol Med Rep, 2015, 12:226-232.
[16] Bartholomeusz C, Gonzalez-Angulo AM. Targeting the PI3K signaling pathway in cancer therapy[J]. Expert Opin Ther Targets, 2012, 16:121-130.
[17] Karthikeyan S, Hoti SL. Development of fourth generation ABC inhibitors from natural products:a novel approach to overcome cancer multidrug resistance[J]. Anticancer Agents Med Chem, 2015, 15:605-615.
[18] Liu YR, Chen JJ, Dai M. Paeonol protects rat vascular endothelial cells from ox-LDL-induced injury in vitro via downregulating microRNA-21 expression and TNF-α release[J]. Acta Pharmacol Sin, 2014, 35:483-488.
[19] Chen YH, Lin PL, Hsu HY, et al. Action potential bursts in central snail neurons elicited by paeonol:roles of ionic currents[J]. Acta Pharmacol Sin, 2010, 31:1553-1563.
[20] Han L, Guo X, Bian H, et al. Guizhi Fuling Wan, a traditional Chinese herbal formula, sensitizes cisplatin-resistant human ovarian cancer cells through inactivation of the PI3K/AKT/mTOR pathway[J]. Evid Based Complement Alternat Med, 2016, 2016:4651949.
[21] Nemade H, Chaudhari U, Acharya A, et al. Cell death mechanisms of the anti-cancer drug etoposide on human cardiomyocytes isolated from pluripotent stem cells[J]. Arch Toxicol, 2018, 92:1507-1524.
[22] Ma J, Xie SL, Geng YJ, et al. In vitro regulation of hepatocellular carcinoma cell viability, apoptosis, invasion, and AEG-1 expression by LY294002[J]. Clin Res Hepatol Gastroenterol, 2014, 38:73-80.
[23] Satonaka H, Ishida K, Takai M, et al. (-)-Epigallocatechin-3-gallate down-regulates doxorubicin-induced overexpression of P-glycoprotein through the coordinate inhibition of PI3K/AKT and MEK/ERK signaling pathways[J]. Anticancer Res, 2017, 37:6071-6077.
[24] Dinesh P, Rasool M. Berberine inhibits IL-21/IL-21R mediated inflammatory proliferation of fibroblast-like synoviocytes through the attenuation of PI3K/AKT signaling pathway and ameliorates IL-21 mediated osteoclastogenesis[J]. Cytokine, 2018, 106:54-66.
[25] Zhao W, Qiu Y, Kong D. Class I phosphatidylinositol 3-kinase inhibitors for cancer therapy[J]. Acta Pharm Sin B, 2017, 7:27-37.
[26] Dei S, Coronnello M, Bartolucci G, et al. Design and synthesis of new potent N,N-bis(arylalkyl)piperazine derivatives as multidrug resistance (MDR) reversing agents[J]. Eur J Med Chem, 2018, 147:7-20.
[27] Yin G, Chen R, Alvero AB, et al. TWISTing stemness, inflammation and proliferation of epithelial ovarian cancer cells through MIR199A2/214[J]. Oncogene, 2010, 29:3545-3553.