Abstract
Eribulin mesylate is a novel, non-taxane, synthetic microtubule inhibitor showing antitumor activity in a wide range of tumors including soft tissue sarcomas (STS). Eribulin has been recently approved for the treatment of metastatic liposarcoma (LPS) patients previously treated with anthracyclines. This work investigated the mechanism of action of this innovative antitubulin agent in well-differentiated/dedifferentiated LPS (ALT/DDLPS) which represents one of the most common adipocytic sarcoma histotypes. A primary culture of ALT/DDLPS from a 54-year-old patient was established. The anticancer activity of eribulin on the patient-derived primary culture was assessed by MTT and tunel assays. Eribulin efficacy was compared to other drugs approved for the treatment of STS. Cell migration and morphology were examined after exposure to eribulin to better understand the drug mechanism of action. Finally, Western blot analysis of apoptosis and migration proteins was performed. The results showed that eribulin exerts its antiproliferative effect by the arrest of cell motility and induction of apoptosis. Our results highlighted the activity of eribulin in the treatment of ALT/DDLPS patients.
Highlights
Eribulin mesylate is a synthetic macrocyclic ketone analogue of the natural compound helichondrin B with an innovative microtubule-inhibitory action.Eribulin was approved in 2010 by the United States Food and Drug Administration (FDA)as a monotherapy for patients with advanced/metastatic breast cancer pretreated with either an anthracycline- or taxane-based regimen [1]
A subsequent computed tomography (CT) scan confirmed the presence of an abdominal lesion of about 5.2 cm with a predominant adipose component located in the small intestine
We demonstrated that the treatment of atypical lipomatous tumor (ALT)/dedifferentiated liposarcoma (DDLPS) resulted in the upregulation of proapototic proteins p-53 and Bax
Summary
Eribulin mesylate is a synthetic macrocyclic ketone analogue of the natural compound helichondrin B with an innovative microtubule-inhibitory action.Eribulin was approved in 2010 by the United States Food and Drug Administration (FDA)as a monotherapy for patients with advanced/metastatic breast cancer pretreated with either an anthracycline- or taxane-based regimen [1]. The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) has recently approved eribulin for the treatment of adult patients with unresectable liposarcoma (LPS) pretreated with an anthracycline-based therapy for metastatic disease. This microtubule-depolymerizing drug exerts an antitumor activity through a mechanism of action different from any other known microtubule inhibitors [2]. Preclinical and clinical studies have shown that eribulin seems to act via a mechanistically unique inhibition of microtubule dynamics, involving the site-specific binding of tubulin. This results in the suppression of microtubule polymerization and tubulin sequestration into non-functional aggregates, and subsequent cell cycle arrest. Other complex effects, including vascular remodeling, reversion of the epithelial-mesenchymal transition and suppression of migration and invasion have been recently described [3,4]
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