Integrating mechanisms of response and resistance against the tubulin binding agent Eribulin in preclinical models of osteosarcoma

Abstract

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.

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer

“…Taken together, these results suggest that parbendazole markedly alters microtubule organization, induces formation of cells with abnormal spindles and drastically interferes with cell cycle progression by promoting G2/M arrest, followed by the emergence of enlarged, polyploid cells. These abnormalities are referred as mitotic catastrophe by several studies [16,17,37,40]. As previously reported, mitotic catastrophe may culminate in apoptosis [16,17].…”

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

“…Drugs that bind β-tubulin have inhibitory effects on microtubule dynamics. Consistent with the disruption of microtubules and the mitotic spindle, MTAs can arrest cell cycle progression in mitosis, resulting in cell death (66,68). …”

Current advances of tubulin inhibitors as dual acting small molecules for cancer therapy

“…There have been tremendous efforts in developing numerous natural and synthetic small molecules capable of binding to and affecting MT dynamics . However, these MT‐targeting agents offer broad diversity in terms of their chemical structures and tubulin protein binding sites, suggesting a potential affinity to bind to proteins other than tubulin . Likewise, many cellular kinases play crucial roles in diverse cellular processes, including cell growth as well as differentiation .…”

“…39,116,121,122,125,126,132 However, these MT-targeting agents offer broad diversity in terms of their chemical structures and tubulin protein binding sites, suggesting a potential affinity to bind to proteins other than tubulin. 39,[133][134][135][136][137][138] Likewise, many cellular kinases play crucial roles in diverse cellular processes, including cell growth as well as differentiation. 139 These findings led to intensive research in kinase modulators resulting in the identification of many kinase inhibitors as anticancer agents.…”