Antitumor effects of BI-D1870 on human oral squamous cell carcinoma.
OBJECTIVE
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.
Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, 40402, Taiwan.
Chang-Fang
CF
Chiu
Li-Yuan
LY
Bai
Naval
N
Kapuriya
Shih-Yuan
SY
Peng
Chia-Yung
CY
Wu
Aaron M
AM
Sargeant
Michael Yuanchien
MY
Chen
Jing-Ru
JR
Weng
D001343:Autophagy / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018613:Microscopy, Confocal; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011621:Pteridines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors; D000077195:Squamous Cell Carcinoma of Head and Neck; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C516541:BI D1870; D011621:Pteridines; D017382:Reactive Oxygen Species; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048051:p38 Mitogen-Activated Protein Kinases