title: Drug-repositioning screening identified piperlongumine as a direct STAT3 inhibitor with potent activity against breast cancer.
abstract: Signal transducer and activator of transcription (STAT) 3 regulates many cardinal features of cancer including cancer cell growth, apoptosis resistance, DNA damage response, metastasis, immune escape, tumor angiogenesis, the Warburg effect and oncogene addiction and has been validated as a drug target for cancer therapy. Several strategies have been used to identify agents that target Stat3 in breast cancer but none has yet entered into clinical use. We used a high-throughput fluorescence microscopy search strategy to identify compounds in a drug-repositioning library (Prestwick library) that block ligand-induced nuclear translocation of Stat3 and identified piperlongumine (PL), a natural product isolated from the fruit of the pepper Piper longum. PL inhibited Stat3 nuclear translocation, inhibited ligand-induced and constitutive Stat3 phosphorylation, and modulated expression of multiple Stat3-regulated genes. Surface plasmon resonance assay revealed that PL directly inhibited binding of Stat3 to its phosphotyrosyl peptide ligand. Phosphoprotein antibody array analysis revealed that PL does not modulate kinases known to activate Stat3 such as Janus kinases, Src kinase family members or receptor tyrosine kinases. PL inhibited anchorage-independent and anchorage-dependent growth of multiple breast cancer cell lines having increased pStat3 or total Stat3, and induced apoptosis. PL also inhibited mammosphere formation by tumor cells from patient-derived xenografts. PL's antitumorigenic function was causally linked to its Stat3-inhibitory effect. PL was non-toxic in mice up to a dose of 30 mg/kg/day for 14 days and caused regression of breast cancer cell line xenografts in nude mice. Thus, PL represents a promising new agent for rapid entry into the clinic for use in treating breast cancer, as well as other cancers in which Stat3 has a role.
authors.affiliation: Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: U
authors.initials: U
authors.lastname: Bharadwaj
authors.affiliation: Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Eckols
authors.affiliation: Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kolosov
authors.affiliation: Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M M
authors.initials: MM
authors.lastname: Kasembeli
authors.affiliation: Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Adam
authors.affiliation: Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: D
authors.initials: D
authors.lastname: Torres
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Dobrolecki
authors.affiliation: 1] Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA [2] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: W
authors.initials: W
authors.lastname: Wei
authors.affiliation: 1] Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA [2] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA [3] Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA [4] Department of Radiology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Lewis
authors.affiliation: The Methodist Cancer Center, The Methodist Hospital Research Institute, Houston, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Dave
authors.affiliation: The Methodist Cancer Center, The Methodist Hospital Research Institute, Houston, TX, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Chang
authors.affiliation: The Methodist Cancer Center, The Methodist Hospital Research Institute, Houston, TX, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Landis
authors.affiliation: Section of Hematology-Oncology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Creighton
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Mancini
authors.affiliation: 1] Section of Infectious Disease, Department of Medicine, Baylor College of Medicine, Houston, TX, USA [2] Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA [3] Department of Radiology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Tweardy
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D049109:Cell Proliferation / Q000187:drug effects; D004148:Dioxolanes / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D058492:Drug Repositioning; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects; D020349:Surface Plasmon Resonance; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D010881:Piperidones
chemical_list: D000970:Antineoplastic Agents; D004148:Dioxolanes; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C498077:piperlongumine; D010881:Piperidones