Anticancer activity of pyrithione zinc in oral cancer cells identified in small molecule screens and xenograft model: Implications for oral cancer therapy

Molecular Oncology - Tập 9 - Trang 1720-1735 - 2015
Gunjan Srivastava1, Ajay Matta1, Guodong Fu1, Raj Thani Somasundaram1, Alessandro Datti2, Paul G. Walfish1,3,4,5,6, Ranju Ralhan1,3,4,6
1Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Mount Sinai Hospital, Toronto, Canada
2Simple Modular Assay and Robotics Technology Facility, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
3Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada
4Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Department of Otolaryngology – Head and Neck Surgery, Mount Sinai Hospital, Toronto, Canada
5Department of Medicine, Endocrine Division, Mount Sinai Hospital and University of Toronto, Toronto, Canada
6Department of Otolaryngology – Head and Neck Surgery, University of Toronto, Toronto, Canada

Tóm tắt

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.

Tài liệu tham khảo

10.1158/0008-5472.CAN-07-6696 10.3390/nu4080875 Audrey R.C.B., 2012, Head and Neck: squamous cell carcinoma: an overview, Atlas Genet. Cytogenet. Oncol. Haematol, 16, 145 10.1093/annonc/mds322 10.1016/j.bbamcr.2011.09.013 10.1007/s00775-010-0736-9 10.1016/j.oraloncology.2006.07.003 10.1046/j.1471-4159.2003.01678.x 10.1016/j.bbamcr.2008.09.010 10.1111/j.1368-5031.2004.00006.x 2012 J. Ferlay I. Soerjomataram M. Ervik R. Dikshit S. Eser C. Mathers M. Rebelo D.M. Parkin D. Forman F. Bray Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 10.1093/carcin/bgl012 10.1038/onc.2011.127 10.1161/HYPERTENSIONAHA.111.203489 10.1016/j.ijrobp.2008.05.024 10.1016/j.oraloncology.2014.06.005 10.1158/0008-5472.CAN-10-2484 10.1016/j.semradonc.2008.09.009 10.1038/nature14129 10.1002/ijc.28473 10.1371/journal.pone.0067361 Kim M.S., 1993, State of p53, Rb and DCC tumor suppressor genes in human oral cancer cell lines, Anticancer Res, 13, 1405 10.1002/ijc.22246 10.1007/s10534-011-9441-6 1999 Kluwer Academic Publishers Norwell MA C.D. Lansford R. Grenman H. Bier K.D. Somers S.Y. Kim T.L. Whiteside G.L. Clayman H.I. Welkoborsky T.E. Carey Head and Neck Cancers 185 255 10.1021/pr101146w 10.1016/j.ijrobp.2007.06.073 10.1002/lary.20524 10.1158/2159-8290.CD-13-0103 10.1186/1471-2407-10-655 10.1093/carcin/bgq278 10.1371/journal.pone.0014728 10.1038/nbt1186 10.1371/journal.pone.0061555 10.1007/0-306-46872-7 10.1158/1535-7163.MCT-10-0312 10.1021/pr7007797 10.1186/1758-3284-1-6 10.1016/j.oraloncology.2008.07.011 10.1158/1078-0432.CCR-11-2824 Myers J.N., 2002, An orthotopic nude mouse model of oral tongue squamous cell carcinoma, Clin. Cancer Res, 8, 293 10.1021/pr800501j 10.2741/s6 10.1038/sj.onc.1209770 10.1016/j.oraloncology.2005.04.010 10.1023/A:1020603110255 Sakai E., 1992, Most human squamous cell carcinomas in the oral cavity contain mutated p53 tumor-suppressor genes, Oncogene, 7, 927 10.1002/ijc.22657 10.1016/j.oraloncology.2008.01.006 10.1016/j.tox.2006.07.027 10.1002/emmm.201000093 2007 T. Soussi Handbook of p53 Mutation in Cell Lines 10.1038/onc.2011.592 10.1038/onc.2011.521 10.1371/journal.pone.0011939 10.1016/j.semcancer.2006.03.004 10.1038/emboj.2012.150 Winter J., 2011, Risk estimation for a malignant transformation of oral lesions by S100A7 and Doc-1 gene expression, Cancer Investig, 29, 478 10.1177/108705719900400206
Thông tin
Thông tin xuất bản

Molecular Oncology

Tập 9

1720-1735

Thông tin tác giả