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

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

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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.

Original languageEnglish (US)
Pages (from-to)804-811
Number of pages8
JournalCarcinogenesis
Volume32
Issue number6
DOIs
StatePublished - Jun 14 2011

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All Science Journal Classification (ASJC) codes

  • Cancer Research

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Lee, H. J., Seo, N. J., Jeong, S. J., Park, Y., Jung, D. B., Koh, W., Lee, H. J., Lee, E. O., Ahn, K. S., Ahn, K. S., Lü, J., & Kim, S. H. (2011). 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. Carcinogenesis, 32(6), 804-811. https://doi.org/10.1093/carcin/bgr015