Abstract
Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-xL was identified as the key regulator of this process. Bcl-xL showed a slower decay curve after protein synthesis disruption that in tolerant cell lines was enough to delay apoptosis, as its action cannot be countered by the relative low levels of pro-apoptotic BH3 proteins BIM and PUMA. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-xL inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-xL targeted therapy arises as a major opportunity to the treatment of STS.
Footnotes
Conflict of Interests: Authors declare no conflict of interests.
Financial support: We thank CERCA Programme / Generalitat de Catalunya for institutional support. S. Rello-Varona was a Marie Curie COFUND-Beatriu De PinÒs Researcher (The European Union 7th Framework Program for R+D and Generalitat de Catalunya, Department for Economy and Knowledge). S. Rello-Varona, M. Fuentes-Guirado and S. García-Monclús were funded by Fundación Alba Pérez lucha contra el cáncer infantil, through a grant endorsed to O.M. Tirado. This work was funded by Instituto de Salud Carlos III: Acción Estratégica de Salud (grants PI12-01908 and PI15-00234 endorsed to X. García del Muro) and co-funded by European Regional Development Fund (ERDF), a way to build Europe.