title: ER maleate is a novel anticancer agent in oral cancer: implications for cancer therapy.
abstract: ER maleate [10-(3-Aminopropyl)-3, 4-dimethyl-9(10H)-acridinone maleate] identified in a kinome screen was investigated as a novel anticancer agent for oral squamous cell carcinoma (OSCC). Our aim was to demonstrate its anticancer effects, identify putative molecular targets and determine their clinical relevance and investigate its chemosensitization potential for platinum drugs to aid in OSCC management. Biologic effects of ER maleate were determined using oral cancer cell lines in vitro and oral tumor xenografts in vivo. mRNA profiling, real time PCR and western blot revealed ER maleate modulated the expression of polo-like kinase 1 (PLK1) and spleen tyrosine kinase (Syk). Their clinical significance was determined in oral SCC patients by immunohistochemistry and correlated with prognosis by Kaplan-Meier survival and multivariate Cox regression analyses. ER maleate induced cell apoptosis, inhibited proliferation, colony formation, migration and invasion in oral cancer cells. Imagestream analysis revealed cell cycle arrest in G2/M phase and increased polyploidy, unravelling deregulation of cell division and cell death. Mechanistically, ER maleate decreased expression of PLK1 and Syk, induced cleavage of PARP, caspase9 and caspase3, and increased chemosensitivity to carboplatin; significantly suppressed tumor growth and increased antitumor activity of carboplatin in tumor xenografts. ER maleate treated tumor xenografts showed reduced PLK1 and Syk expression. Clinical investigations revealed overexpression of PLK1 and Syk in oral SCC patients that correlated with disease prognosis. Our in vitro and in vivo findings provide a strong rationale for pre-clinical efficacy of ER maleate as a novel anticancer agent and chemosensitizer of platinum drugs for OSCC.
authors.affiliation: Department of Medicine, Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Endocrine Division, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Guodong
authors.initials: G
authors.lastname: Fu
authors.affiliation: Department of Medicine, Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Endocrine Division, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Raj Thani
authors.initials: RT
authors.lastname: Somasundaram
authors.affiliation: Department of Medicine, Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Endocrine Division, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Fatima
authors.initials: F
authors.lastname: Jessa
authors.affiliation: Department of Medicine, Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Endocrine Division, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Gunjan
authors.initials: G
authors.lastname: Srivastava
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.
authors.forename: Christina
authors.initials: C
authors.lastname: MacMillan
authors.affiliation: Department of Otolaryngology - Head and Neck Surgery, Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, Toronto, Canada.|Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, Canada.
authors.forename: Ian
authors.initials: I
authors.lastname: Witterick
authors.affiliation: Department of Medicine, Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Endocrine Division, Mount Sinai Hospital, Toronto, Canada.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.|Department of Otolaryngology - Head and Neck Surgery, Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, 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: Department of Medicine, Alex and Simona Shnaider Research Laboratory in Molecular Oncology, Endocrine Division, Mount Sinai Hospital, Toronto, Canada.|Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada.|Department of Otolaryngology - Head and Neck Surgery, Joseph and Mildred Sonshine Family Centre for Head and Neck Diseases, Mount Sinai Hospital, Toronto, Canada.|Department of Otolaryngology - Head and Neck Surgery, University of Toronto, Toronto, Canada.
authors.forename: Ranju
authors.initials: R
authors.lastname: Ralhan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000077195:Squamous Cell Carcinoma of Head and Neck; D000072377:Syk Kinase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000072377:Syk Kinase; D000097869:Polo-Like Kinase 1; C000606896:SYK protein, human
keywords: ER maleate; OSCC; Syk / PLK1; anticancer agent; tumor xenografts