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.
Highlights
Oral squamous cell carcinoma (OSCC) is the major subset of head and neck cancer, which ranks as the sixth most common cancer worldwide [1]
We observed downregulation of Polo-like kinase 1 (PLK1), Spleen tyrosine kinase (Syk) and Cell cycle check point kinase 2 (CHEK2) in ER maleate treated cells that may account for deregulation of cell division
PLK1 is overexpressed during cancer development and plays a critical role in cell division as a major cell cycle regulator controlling entry into mitosis and regulating the spindle checkpoint [21, 22]
Summary
Oral squamous cell carcinoma (OSCC) is the major subset of head and neck cancer, which ranks as the sixth most common cancer worldwide [1]. Head and neck cancer patients diagnosed at stages I and II have five-year survival rates of 70% – 90% [2,3,4], while those diagnosed in stages III and IV have 50% survival, limited treatment options and poor prognosis [5]. Current treatments including primary surgery and/or a combination of chemo- and radio- therapy for OSCC patients are traumatic, disfiguring and drastically compromise their quality of life [6]. Chemotherapy (CT) using cisplatin/ carboplatin, methotrexate or taxanes as single agents or in combination are given in recurrent or metastatic head and neck cancer; dose-limiting toxicities restrict their clinical utility [3, 7,8,9,10]. Using quantitative high throughput assays, ER 27319 maleate [10-(3-Aminopropyl)3,4-dimethyl-9(10H)-acridinone maleate] (ER maleate) was identified as one of the most effective cytotoxic agents for OSCC by screening six chemical libraries containing 5170 small molecule inhibitors [15]
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