Oral administration of penta-O-galloyl-β-D-glucose suppresses triple-negative breast cancer xenograft growth and metastasis in strong association with JAK1-STAT3 inhibition

• Published in: Carcinogenesis (New York) 2011-06, Vol.32 (6), p.804-811
• Main Authors: LEE, Hyo-Jeong, SEO, Nam-Jun, LÜ, Junxuan, KIM, Sung-Hoon, JEONG, Soo-Jin, PARK, Yongjin, JUNG, Deok-Beom, KOH, Wonil, LEE, Hyo-Jung, LEE, Eun-Ok, KWANG SEOK AHN, KYOO SEOK AHN
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Apoptosis - drug effects; Biological and medical sciences; Blotting, Western; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Breast Neoplasms - prevention & control; Cancer Biology; Carcinogenesis, carcinogens and anticarcinogens; Cell Proliferation - drug effects; Electrophoretic Mobility Shift Assay; Female; Gynecology. Andrology. Obstetrics; Humans; Hydrolyzable Tannins - administration & dosage; Immunoenzyme Techniques; Janus Kinase 1 - antagonists & inhibitors; Janus Kinase 1 - genetics; Janus Kinase 1 - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Mammary gland diseases; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Receptor, ErbB-2 - metabolism; Receptors, Estrogen - metabolism; Receptors, Progesterone - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; STAT3 Transcription Factor - antagonists & inhibitors; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgr015

There is an urgent clinical need for chemotherapeutic and chemopreventive drugs for triple-negative breast cancer (TNBCa). Extending on our recent work, we hypothesize that the herbal compound 1,2,3,4,6-penta-O-galloyl-beta-D-glucose (PGG) can inhibit the growth and metastasis of TNBCa xenograft and target Janus-activated kinase (JAK)-signal transducer and activator of transcription (STAT) 3-signaling axis. Daily oral gavage of 10 mg PGG/kg body wt decreased MDA-MB-231 xenograft weight by 49.3% (P < 0.01) at 40 days postinoculation, whereas weekly intraperitoneal injections of Taxol at the same dosage resulted in a 21.4% reduction (P > 0.1). PGG treatment also decreased the incidence of lung metastasis. Immunohistochemical staining detected decreased Ki-67 (proliferation) index and increased terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (apoptosis) index in PGG-treated and Taxol-treated xenografts. However, the CD34 (angiogenesis) index was decreased only in PGG-treated xenografts along with decreased phospho-STAT3. In cell culture of MDA-MB-231 cells, PGG decreased pSTAT3 and its downstream target proteins, decreased its upstream kinase pJAK1 and induced the expression of SHP1, a JAK1 upstream tyrosine phosphatase, within as early as 1 h of exposure. The phosphatase inhibitor pervanadate reversed the PGG-induced downregulation of pSTAT3 and caspase activation. Orally administered PGG can inhibit TNBCa growth and metastasis, probably through anti-angiogenesis, antiproliferation and apoptosis induction. Mechanistically, PGG-induced inhibition of JAK1-STAT3 axis may contribute to the observed in vivo efficacy and the effects on the cellular processes.