title: Benefits of Multifaceted Chemopreventives in the Suppression of the Oral Squamous Cell Carcinoma (OSCC) Tumorigenic Phenotype.
abstract: Over one third of patients who have undergone oral squamous cell carcinoma (OSCC) surgical resections develop life-threatening and often untreatable recurrences. A variety of drugs, intended for management of recurrent or disseminated cancers, were designed to exploit cancer cells' reliance upon overexpressed receptors and gratuitous signaling. Despite their conceptual promise, clinical trials showed these agents lacked efficacy and were often toxic. These findings are consistent with evasion of pathway-targeted treatments via extensive signaling redundancies and compensatory mechanisms common to cancers. Optimal secondary OSCC chemoprevention requires long-term efficacy with multifaceted, nontoxic agents. Accordingly, this study evaluated the abilities of three complementary chemopreventives, that is, the vitamin A derivative fenretinide (4-HPR, induces apoptosis and differentiation, inhibits signaling proteins, and invasion), the estrogen metabolite 2-methoxyestradiol (2-ME, apoptosis-inducing, antiangiogenic), and the humanized mAb to the IL6R receptor tocilizumab (TOC, reduces IL6 signaling) to suppress OSCC gratuitous signaling and tumorigenesis. Modeling studies demonstrated 4-HPR's high-affinity binding at STAT3's dimerization site and c-Abl and c-Src ATP-binding kinase sites. Although individual agents suppressed cancer-promoting pathways including STAT3 phosphorylation, STAT3-DNA binding, and production of the trans-signaling enabling sIL6R, maximal chemopreventive effects were observed with agent combinations. OSCC tumor xenograft studies showed that locally delivered TOC, TOC+4-HPR, and TOC+4-HPR+2-ME treatments all prevented significant tumor growth. Notably, the TOC+4-HPR+2-ME treatment resulted in the smallest overall increase in tumor volume. The selected agents use diverse mechanisms to disrupt tumorigenesis at multiple venues, that is, intracellular, tumor cell-ECM, and tumor microenvironment; beneficial qualities for secondary chemopreventives. Cancer Prev Res; 10(1); 76-88. ©2016 AACR.
authors.affiliation: Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio. mallery.1@osu.edu.|The Ohio State University Comprehensive Cancer, Columbus, Ohio.
authors.forename: Susan R
authors.initials: SR
authors.lastname: Mallery
authors.affiliation: Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio.
authors.forename: Daren
authors.initials: D
authors.lastname: Wang
authors.affiliation: Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio.
authors.forename: Brian
authors.initials: B
authors.lastname: Santiago
authors.affiliation: Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio.
authors.forename: Ping
authors.initials: P
authors.lastname: Pei
authors.affiliation: College of Pharmacy, University of Michigan, North Campus Research Complex, Ann Arbor, Michigan.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Schwendeman
authors.affiliation: College of Pharmacy, University of Michigan, North Campus Research Complex, Ann Arbor, Michigan.
authors.forename: Kari
authors.initials: K
authors.lastname: Nieto
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio.
authors.forename: Richard
authors.initials: R
authors.lastname: Spinney
authors.affiliation: Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio.
authors.forename: Meng
authors.initials: M
authors.lastname: Tong
authors.affiliation: Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio.
authors.forename: George
authors.initials: G
authors.lastname: Koutras
authors.affiliation: Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio.
authors.forename: Brian
authors.initials: B
authors.lastname: Han
authors.affiliation: Division of Oral Maxillofacial Pathology & Radiology, College of Dentistry, The Ohio State University, Columbus, Ohio.
authors.forename: Andrew
authors.initials: A
authors.lastname: Holpuch
authors.affiliation: The Ohio State University Comprehensive Cancer, Columbus, Ohio.|Department of Otolaryngology, College of Medicine, Ohio State University, Columbus, Ohio.
authors.forename: James
authors.initials: J
authors.lastname: Lang
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004958:Estradiol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D017313:Fenretinide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D010641:Phenotype; D010766:Phosphorylation; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016588:Anticarcinogenic Agents; C508603:IL6R protein, human; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D017313:Fenretinide; D004958:Estradiol; D000077584:2-Methoxyestradiol; C502936:tocilizumab