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.

Abstract

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.

• Authors: Hyo-Jeong Lee, Nam-Jun Seo, Soo-Jin Jeong, Yongjin Park, Deok-Beom Jung, Wonil Koh, Hyo-Jung Lee, Eun-Ok Lee, Kwang Seok Ahn, Kyoo Seok Ahn, Junxuan Lü, Sung-Hoon Kim
• Journal: Carcinogenesis (Carcinogenesis) Vol. 32 Issue 6 Pg. 804-11 (Jun 2011) ISSN: 1460-2180 [Electronic] England
• PMID: 21289371 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hydrolyzable Tannins
• RNA, Messenger
• RNA, Small Interfering
• Receptors, Estrogen
• Receptors, Progesterone
• STAT3 Transcription Factor
• Stat3 protein, mouse
• pentagalloylglucose
• Receptor, ErbB-2
• Jak1 protein, mouse
• Janus Kinase 1
• Sodium-Potassium-Exchanging ATPase

Topics

• Animals
• Apoptosis (drug effects)
• Blotting, Western
• Breast Neoplasms (drug therapy, pathology, prevention & control)
• Cell Proliferation (drug effects)
• Electrophoretic Mobility Shift Assay
• Female
• Humans
• Hydrolyzable Tannins (administration & dosage)
• Immunoenzyme Techniques
• Janus Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Lung Neoplasms (drug therapy, prevention & control, secondary)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Receptor, ErbB-2 (metabolism)
• Receptors, Estrogen (metabolism)
• Receptors, Progesterone (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (antagonists & inhibitors)
• Sodium-Potassium-Exchanging ATPase (antagonists & inhibitors)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays