New target structure in neuroblastoma therapy: CBSIs are effective against Vincristine resistance

The treatment of high-risk neuroblastoma faces a therapeutic hurdle: around half of high-risk neuroblastomas do not respond adequately to initial chemotherapy or suffer a relapse. A key reason for this is resistance to the tubulin inhibitor vincristine, a standard drug used in first-line therapy.

In a recent study (click Link), the efficacy of novel colchicine binding site inhibitors (CBSIs) was analysed in vincristine-resistant neuroblastoma cell lines. The study used cell lines from the RCCL collection. Unlike vincristine, CBSIs bind to an alternative domain of the tubulin molecule – thus bypassing classic resistance mechanisms such as ABC transporter-mediated drug elimination or βIII tubulin overexpression.

Key findings:

• Two substances, 4h and 4k, showed dose-dependent inhibition of cell growth in vincristine-resistant and -sensitive lines.
• Both CBSIs induced G2/M cell cycle blockade, confirming their anti-mitotic effect.
• 4h proved to be more potent in almost all assays – including apoptosis induction in MYCN-amplified resistances.
• Differences in the apoptosis response indicate cell type-specific resilience mechanisms that could be specifically addressed in the future.

Why this is relevant: CBSIs open up a new therapeutic approach for relapse patients with resistant neuroblastoma – beyond classic vinca alkaloids. They could represent an option if established therapies fail and substantially expand the therapeutic arsenal for this complex tumour.

Foto: Creative Commons Namensnennung (CC BY) Lizenz (https://creativecommons.org/licenses/by/4.0/)