ER maleate is a novel anticancer agent in oral cancer: implications for cancer therapy

• Published in: Oncotarget 2016-03, Vol.7 (13), p.17162-17181
• Main Authors: Fu, Guodong, Somasundaram, Raj Thani, Jessa, Fatima, Srivastava, Gunjan, MacMillan, Christina, Witterick, Ian, Walfish, Paul G, Ralhan, Ranju
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - mortality; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - biosynthesis; Cell Movement - drug effects; Cell Proliferation - drug effects; Female; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - enzymology; Head and Neck Neoplasms - mortality; Humans; Kaplan-Meier Estimate; Male; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Mouth Neoplasms - drug therapy; Mouth Neoplasms - enzymology; Mouth Neoplasms - mortality; Polo-Like Kinase 1; Protein Kinase Inhibitors - pharmacology; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - biosynthesis; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - biosynthesis; Research Paper; Squamous Cell Carcinoma of Head and Neck; Syk Kinase - antagonists & inhibitors; Syk Kinase - biosynthesis; Xenograft Model Antitumor Assays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.7751

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.