title: Combined treatment with chrysin and 1,2,3,4,6-penta-O-galloyl-β-D-glucose synergistically inhibits LRP6 and Skp2 activation in triple-negative breast cancer and xenografts.
abstract: Triple-negative breast cancer (TNBC) is difficult to treat because there is no targeted therapy available. Clinical studies have demonstrated that S-phase kinase-associated protein 2 (Skp2) and low-density lipoprotein receptor-related protein 6 (LRP6) are highly expressed in TNBC. Therefore, therapeutic strategies designed to downregulate LRP6 or Skp2 may play an important clinical role in the treatment of TNBC. However, the regulatory effects of many drugs on Skp2 and LRP6 expression are currently unknown. In the present study, combined treatment with chrysin and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (5GG) synergistically induced apoptosis and cell cycle arrest and inhibited cell proliferation and colony formation in AU565 and MDA-MB-231 human breast cancer cells. Furthermore, the combination of chrysin and 5GG suppressed tumor growth in nude mice with xenografted MDA-MB-231 cells by downregulating the phospho-LRP6 (pLRP6) and Skp2 proteins. Overall, our findings suggested that the combination of chrysin and 5GG has a potential therapeutic value in treating breast cancer, particularly for TNBC associated with Skp2/LRP6 overexpression, and hence warrants further investigation.
authors.affiliation: National Research Institute of Chinese Medicine, Taipei, Taiwan, ROC.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan, ROC.
authors.forename: Yi Jing
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan, ROC.|Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Chen
authors.affiliation: Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC.|Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: Chih-Li
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan, ROC.
authors.forename: Yu Xuan
authors.initials: YX
authors.lastname: Wei
authors.affiliation: Department of Applied Science, National Hsinchu University of Education, Hsinchu, Taiwan, ROC.
authors.forename: Hsiu Chen
authors.initials: HC
authors.lastname: Huang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000032:analysis*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D044786:S-Phase Kinase-Associated Proteins / Q000037:antagonists & inhibitors*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
chemical_list: D005419:Flavonoids; D047348:Hydrolyzable Tannins; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D044786:S-Phase Kinase-Associated Proteins; C043561:chrysin; C435084:pentagalloylglucose
keywords: 1,2,3,4,6-penta-O-galloyl-β-D-glucose; LRP6; Skp2; chrysin; triple negative breast cancer; xenografts