Podophyllotoxin reduces the aggressiveness of human oral squamous cell carcinoma through myeloid cell leukemia-1

Podophyllotoxin (PPT), which is derived from the podophyllum plant, exhibits marked cytotoxic effects against cancer cells; however, the precise molecular mechanism underlying its activity against human oral squamous cell carcinoma (OSCC) has not been elucidated. In the present study, the mechanism by which PPT induced cytotoxicity in two OSCC cell lines, HSC3 and HSC4, was determined. The effects of PPT on cytotoxicity in HSC3 and HSC4 cells were analyzed using Annexin V/PI double staining, Sub-G(1) analysis, soft agar assays, western blotting, and quantitative PCR. The changes in the mitochondrial membrane potential were assessed using a JC-1 assay and cytosolic and mitochondrial fractionation. A myeloid cell leukemia-1 (Mcl-1) overexpression cell lines were also established to study the role of Mcl-1 on apoptosis. The results showed that PPT inhibited the growth of the two human OSCC cell lines and induced apoptosis, which was accompanied by mitochondrial membrane depolarization. Compared with the control, PPT reduced the expression of Mcl-1 in both cell lines through a proteasome-dependent protein degradation process. Overall, these results suggested that targeting of Mcl-1 protein by PPT induced apoptosis, providing a foundation for further pre-clinical and clinical study of its value in the management of OSCC.