Osteosarcoma is the most frequently occurring bone cancer in children and adolescents. Unfortunately, treatment failures are common. Eribulin is a synthetic microtubule inhibitor that has demonstrated activity in preclinical osteosarcoma models. The effects of eribulin were evaluated in two human osteosarcoma cell lines as well as in eribulin-sensitive and -resistant osteosarcoma xenograft tumors of the Pediatric Preclinical Testing Program (PPTP) by characterizing cell viability, microtubule destabilization, mitotic arrest and mechanism of cell death. Eribulin demonstrated cytotoxic activity in vitro, through promotion of microtubule dynamic instability, arrest of cells in the G2/M phase, mitotic catastrophe and cell death. The microtubule-destabilizing protein stathmin-1 (STMN1) was coimmunoprecipitated with the cyclin-dependent kinase inhibitor p27 indicating that these cytoplasmic complexes can protect cells from the microtubule destabilizing effect of eribulin. Increased tumoral expression of P-glycoprotein (P-gp) and TUBB3 were also associated with lower drug sensitivity. In summary, eribulin successfully blocked cells in G2/M phase but interfered with mitochondria activity to inhibit proteins involved in apoptosis. Understanding the complex and inter-related mechanisms involved in the overall drug response to eribulin may help in the design of therapeutic strategies that enhance drug activity and improve benefits of eribulin in pediatric patients with osteosarcoma.
Darnella Frazer, a teenage witness to a fatal police encounter, used social media to share her cell phone video footage capturing a white police officer casually kneeling on the neck of a handcuffed Black man named George Floyd for nearly nine minutes. Her video rapidly went viral, sparking civil unrest across the United States (US) and protests around the world.1 Independent experts of the Special Procedures of the United Nations Human Rights Council came together to issue a joint statement condemning ‘systemic racism’ and ‘state sponsored racial violence’ in the US.2 George Floyd was not the first unarmed Black person to die in police custody under questionable circumstances,3 but his murder motivated many to confront the reality of racism in American society. A broad section of the business community reacted to the civil unrest in the immediate aftermath of the murder of George Floyd with solidarity statements denouncing racism and pledges to promote racial equality.4 Brands rushed to embrace the previously untouchable #BlackLivesMatter movement in marketing campaigns. Business leaders expressed interested in evaluating how particular policies and practices operate in ways that serve to promote racial discrimination or perpetuate racial inequality.5
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