title: Anticancer activity of pyrithione zinc in oral cancer cells identified in small molecule screens and xenograft model: Implications for oral cancer therapy.
abstract: Oral squamous cell carcinoma (OSCC) patients diagnosed in late stages have limited chemotherapeutic options, underscoring the great need for development of new anticancer agents for more effective disease management. We aimed to identify novel anticancer agents for OSCC using quantitative high throughput assays for screening six chemical libraries consisting of 5170 small molecule inhibitors. In depth characterization resulted in identification of pyrithione zinc (PYZ) as the most effective cytotoxic agent inhibiting cell proliferation and inducing apoptosis in OSCC cells in vitro. Further, treatment with PYZ reduced colony forming, migration and invasion potential of oral cancer cells in a dose-dependent manner. PYZ treatment also led to altered expression of several key components of the major signaling pathways including PI3K/AKT/mTOR and WNT/β-catenin in OSCC cells. In addition, treatment with PYZ also reduced expression of 14-3-3ζ, 14-3-3σ, cyclin D1, c-Myc and pyruvate kinase M2 (PKM2), proteins identified in our earlier studies to be involved in development and progression of OSCCs. Importantly, PYZ treatment significantly reduced tumor xenograft volume in immunocompromised NOD/SCID/Crl mice without causing apparent toxicity to normal tissues. Taken together, we demonstrate in vitro and in vivo efficacy of PYZ in OSCC. In conclusion, we identified PYZ in HTS assays and demonstrated in vitro and in vivo pre-clinical efficacy of PYZ as a novel anticancer therapeutic candidate in OSCC.
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Gunjan
authors.initials: G
authors.lastname: Srivastava
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Ajay
authors.initials: A
authors.lastname: Matta
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Guodong
authors.initials: G
authors.lastname: Fu
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Raj Thani
authors.initials: RT
authors.lastname: Somasundaram
authors.affiliation: Simple Modular Assay and Robotics Technology Facility, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Datti
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada; Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology - Head and Neck Surgery, Mount Sinai Hospital, Toronto, Canada; Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto, Toronto, Canada; Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, Canada.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Walfish
authors.affiliation: Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada; Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada; Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology - Head and Neck Surgery, Mount Sinai Hospital, Toronto, Canada; Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, Canada. Electronic address: rralhan@mtsinai.on.ca.
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009361:Neoplasm Invasiveness; D009942:Organometallic Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000032:analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011725:Pyridines; D054852:Small Molecule Libraries; C010423:pyrithione zinc
keywords: Anticancer agent; High throughput screening; Oral cancer; Pyrithione zinc; Tumor xenografts