Piperlongumine Induces Apoptosis and Synergizes with Doxorubicin by Inhibiting the JAK2-STAT3 Pathway in Triple-Negative Breast Cancer

被引:38
作者
Chen, Di [1 ,2 ,3 ]
Ma, Yangmin [1 ]
Li, Peiqi [3 ]
Liu, Meng [3 ]
Fang, Yuan [3 ]
Zhang, Jiejie [3 ]
Zhang, Bilin [3 ]
Hui, Yuyu [1 ]
Yin, Yue [4 ]
机构
[1] Shaanxi Univ Sci & Technol, Shaanxi Key Lab Chem Addit Ind, Xian 710021, Shaanxi, Peoples R China
[2] Shaanxi Univ Sci & Technol, Sch Food & Biol Engn, Xian 710021, Shaanxi, Peoples R China
[3] Xian Med Univ, Inst Basic Med Sci, Xian 710021, Shaanxi, Peoples R China
[4] Xi An Jiao Tong Univ, Hlth Sci Ctr, Sch Publ Hlth, Xian 710061, Shaanxi, Peoples R China
来源
MOLECULES | 2019年 / 24卷 / 12期
基金
中国国家自然科学基金;
关键词
triple-negative breast cancer; piperlongumine; doxorubicin; apoptosis; JAK2; STAT3; STAT3; ACTIVATION; TUMOR-CELLS; SURVIVAL; STRESS; GROWTH;
D O I
10.3390/molecules24122338
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Triple-negative breast cancer (TNBC) lacks major effective target molecules and chemotherapy remains the current main treatment. However, traditional chemotherapy drugs, such as doxorubicin (DOX), cause serious side effects and have a poor prognosis. Piperlongumine (PL), a natural alkaloid, has showed selective anticancer effects and is expected to become a new strategy against TNBC. In our research, cell viability, colony formation, flow cytometry, Western blot, and tumor xenograft model assays were established to evaluate the suppression effect of PL and DOX alone and in combination. Data showed that PL could effectively inhibit cell growth and induce apoptosis in two TNBC cell lines. We also demonstrated for the first time that the combination treatment of PL and DOX synergistically inhibited cell growth and induced apoptosis in TNBC cells. The suppression of STAT3 activation was indicated to be a mechanism of the anticancer effect. Moreover, the effectiveness of this combination was confirmed in a tumor xenograft model. These results revealed that inhibition of the JAK2-STAT3 pathway was a key anticancer mechanism when treated with PL alone or combined with DOX, suggesting that the combination of PL and chemotherapy drugs may be a potential strategy for the clinical treatment of TNBC.
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页数:15
相关论文
共 35 条
[1]   Overview of the therapeutic potential of piplartine (piperlongumine) [J].
Bezerra, Daniel P. ;
Pessoa, Claudia ;
de Moraes, Manoel O. ;
Saker-Neto, Nicolau ;
Silveira, Edilberto R. ;
Costa-Lotufo, Leticia V. .
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2013, 48 (03) :453-463
[2]   Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer [J].
Bharadwaj, U. ;
Eckols, T. K. ;
Kolosov, M. ;
Kasembeli, M. M. ;
Adam, A. ;
Torres, D. ;
Zhang, X. ;
Dobrolecki, L. E. ;
Wei, W. ;
Lewis, M. T. ;
Dave, B. ;
Chang, J. C. ;
Landis, M. D. ;
Creighton, C. J. ;
Mancini, M. A. ;
Tweardy, D. J. .
ONCOGENE, 2015, 34 (11) :1341-1353
[3]   Measures of Outcome in Metastatic Breast Cancer: Insights From a Real-World Scenario [J].
Bonotto, Marta ;
Gerratana, Lorenzo ;
Poletto, Elena ;
Driol, Pamela ;
Giangreco, Manuela ;
Russo, Stefania ;
Minisini, Alessandro M. ;
Andreetta, Claudia ;
Mansutti, Mauro ;
Pisa, Federica E. ;
Fasola, Gianpiero ;
Puglisi, Fabio .
ONCOLOGIST, 2014, 19 (06) :608-615
[4]   ALKALOIDS OF PIPER LONGUM LINN .I. STRUCTURE AND SYNTHESIS OF PIPERLONGUMINE AND PIPERLONGUMININE [J].
CHATTERJEE, A ;
DUTTA, CP .
TETRAHEDRON, 1967, 23 (04) :1769-+
[5]   JAK-STAT signalling controls cancer stem cell properties including chemotherapy resistance in myxoid liposarcoma [J].
Dolatabadi, Soheila ;
Jonasson, Emma ;
Linden, Malin ;
Fereydouni, Bentolhoda ;
Backsten, Karin ;
Nilsson, Malin ;
Martner, Anna ;
Forootan, Amin ;
Fagman, Henrik ;
Landberg, Goran ;
Aman, Pierre ;
Stahlberg, Anders .
INTERNATIONAL JOURNAL OF CANCER, 2019, 145 (02) :435-449
[6]   BCL-2 proteins and apoptosis: Recent insights and unknowns [J].
Edlich, Frank .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2018, 500 (01) :26-34
[7]   Effective down-regulation of signal transducer and activator of transcription 3 (STAT3) by polyplexes of siRNA and lipid-substituted polyethyleneimine for sensitization of breast tumor cells to conventional chemotherapy [J].
Falamarzian, Arash ;
Aliabadi, Hamidreza Montazeri ;
Molavi, Ommoleila ;
Seubert, John M. ;
Lai, Raymond ;
Uludag, Hasan ;
Lavasanifar, Afsaneh .
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A, 2014, 102 (09) :3216-3228
[8]   Piperlongumine Inhibits NF-κB Activity and Attenuates Aggressive Growth Characteristics of Prostate Cancer Cells [J].
Ginzburg, Serge ;
Golovine, Konstantin V. ;
Makhov, Petr B. ;
Uzzo, Robert G. ;
Kutikov, Alexander ;
Kolenko, Vladimir M. .
PROSTATE, 2014, 74 (02) :177-186
[9]   Piperlongumine Induces Apoptosis and Synergizes with Cisplatin or Paclitaxel in Human Ovarian Cancer Cells [J].
Gong, Li-Hua ;
Chen, Xiu-Xiu ;
Wang, Huan ;
Jiang, Qi-Wei ;
Pan, Shi-Shi ;
Qiu, Jian-Ge ;
Mei, Xiao-Long ;
Xue, You-Qiu ;
Qin, Wu-Ming ;
Zheng, Fei-Yun ;
Shi, Zhi ;
Yan, Xiao-Jian .
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, 2014, 2014
[10]   Piperlongumine Chemosensitizes Tumor Cells through Interaction with Cysteine 179 of IκBα Kinase, Leading to Suppression of NF-κB-Regulated Gene Products [J].
Han, Jia Gang ;
Gupta, Subash C. ;
Prasad, Sahdeo ;
Aggarwal, Bharat B. .
MOLECULAR CANCER THERAPEUTICS, 2014, 13 (10) :2422-2435