In Vitro and In Vivo Effects of the Urokinase Plasminogen Activator Inhibitor WX-340 on Anaplastic Thyroid Cancer Cell Lines

Abstract

Increased expression of the urokinase-type plasminogen activator (uPA) system is associated with tumor invasion, neo-angiogenesis, and metastatic spread, and has been shown to positively correlate with a poor prognosis in several cancer types, including thyroid carcinomas. In recent years, several uPA inhibitors were found to have anticancer effects in preclinical studies and in some phase II clinical trials, which prompted us to evaluate uPA as a potential therapeutic target for the treatment of patients affected by the most aggressive form of thyroid cancer, the anaplastic thyroid carcinoma (ATC). In this study, we evaluated the in vitro and in vivo effects of WX-340, a highly specific and selective uPA inhibitor, on two ATC-derived cell lines, CAL-62 and BHT-101. The results obtained indicated that WX-340 was able to reduce cell adhesion and invasiveness in a dose-dependent manner in both cell lines. In addition, WX-340 increased uPA receptor (uPAR) protein levels without affecting its plasma membrane concentration. However, this compound was unable to significantly reduce ATC growth in a xenograft model, indicating that uPA inhibition alone may not have the expected therapeutic effects.

Advanced Differentiated Thyroid Cancer: A Complex Condition Needing a Tailored Approach

“…Therapy should be repeated at least 6-12 months after the previous treatment (5). Finally, systemic therapy may be considered in patients with locally advanced and/or metastatic RAI refractory disease not suitable for local therapies with the purpose to reduce tumour growth and/or metastatic spread (43). The first-line systemic therapy is represented by the multikinase inhibitors lenvatinib and sorafenib, approved by FDA and EMA (44)(45)(46)(47)(48)(49).…”

Risk Factors for Anaplastic Thyroid Carcinoma: A Case Series From a Tertiary Referral Center for Thyroid Surgery and Literature Analysis

“…Although any DTC type can be found in association with ATC, papillary cancer is the most common ( 8 , 10 , 26 , 28 , 32 , 38 ). Within papillary cancer, the biologically more aggressive forms (insular and high cell type) are most commonly found associated with ATC, reinforcing the theory of neoplastic transformation.…”

“…Increased expression of the urokinase-type plasminogen activator (uPA) system has been reported to be associated with tumor invasion, neo-angiogenesis, and metastatic spread in thyroid cancers, and Aurora kinases are associated with severe mitotic abnormalities. Based on this evidence, uPA and Aurora kinases are considered potential therapeutic targets for the treatment of ATC ( 38 , 39 ).…”

Is Melanoma Progression Affected by Thyroid Diseases?

“…However, patients affected by PDTC or ATC do not respond to any treatment currently available, and have a dismal prognosis [ 36 ]. For these tumors, new therapeutic approaches based on selective tyrosine kinase inhibitors or immunotherapy are currently under clinical evaluation [ 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”