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Cancer Chemotherapy and Pharmacology

Erschienen in:

16.10.2021 | Original Article

Abemaciclib is synergistic with doxorubicin in osteosarcoma pre-clinical models via inhibition of CDK4/6–Cyclin D–Rb pathway

verfasst von: Deli Wang, Haiqin Bao

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 1/2022

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Abstract

Background

Osteosarcoma is a prevalent type of bone tumor in children and adolescents, with limited treatment and poor prognosis. Abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), is approved for the treatment of advanced breast cancer as single agent therapy and is currently under investigation in clinical trials for the treatment of several solid tumors.

Methods

The efficacy of abemaciclib was determined using osteosarcoma cellular assays and xenograft mouse model. The combination studies were performed based on the Chou-Talalay method. Immunoblotting analysis was performed to determine the underlying mechanisms of abemaciclib in osteosarcoma cell lines.

Results

Abemaciclib potently inhibits growth, anchorage-independent colony formation and survival of a panel of osteosarcoma cell lines, with IC50 range from 90 nM to >20 μM. In addition, the combination of abemaciclib and doxorubicin is synergistic and antagonistic in abemaciclib-sensitive (IC50 <1 μM) and abemaciclib-resistant (IC50 >1 μM), respectively. Abemaciclib inhibits tumor formation and growth in a dose-dependent manner without causing significant drug toxicity in mice. The combination of abemaciclib and doxorubicin results in much greater efficacy than doxorubicin alone in inhibiting tumor growth throughout the whole treatment duration. Abemaciclib acts on osteosarcoma via suppressing CDK4/6-Cyclin D-Rb pathway.

Conclusions

Our pre-clinical evidence provides a rationale of initializing clinical trial of investigating the efficacy of abemaciclib in combination with doxorubicin in osteosarcoma patients. Our work also highlights the therapeutic value of CDK4/6 inhibition in osteosarcoma with proper function of Rb.

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Titel: Abemaciclib is synergistic with doxorubicin in osteosarcoma pre-clinical models via inhibition of CDK4/6–Cyclin D–Rb pathway
verfasst von: Deli Wang
Haiqin Bao
Publikationsdatum: 16.10.2021
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 1/2022
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-021-04363-6

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