Antitumor effects of BI-D1870 on human oral squamous cell carcinoma.

Purpose: Among the signaling pathways implicated in the tumorigenesis of oral squamous cell carcinoma (OSCC) is the extracellular signal-regulated kinase mitogen-activated protein kinase pathway, a downstream target of which is a family of serine/threonine kinases known as the 90 kDa ribosomal S6 kinases (RSKs). This study aims to investigate the role of BI-D1870, a specific inhibitor of p90 RSKs, in a panel of OSCC cell lines. Methods: The antitumor effects and mechanisms of BI-D1870 were assessed by MTT assays, flow cytometry, Western blotting, transfection, and confocal microscopy. Results: BI-D1870 exhibited a dose-responsive antiproliferative effect on OSCC cells with relative sparing of normal human oral keratinocytes. The compound inhibited the downstream RSK target YB-1 and caused apoptosis as evidenced by PARP cleavage, activation of the caspase cascade, and the presence of pyknotic nuclei in the 4,6-diamidino-2-phenylindole assay. In addition, BI-D1870 also induced G2/M arrest by modulating the expression of p21 and other cell cycle regulators. Other newly discovered anticancer attributes of BI-D1870 included the generation of reactive oxygen species and increases in endoplasmic reticulum stress and autophagy. Conclusions: Together, these results suggest the translational value of BI-D1870 in oral squamous cell carcinoma therapy. [ABSTRACT FROM AUTHOR]