Apogossypolone (ApoG2) induces ROS-dependent apoptosis and reduces invasiveness of PC12 cells in vitro and in vivo

Malignant pheochromocytoma is accurately diagnosed only at occurrence of metastatic foci. However, at that time, patients are less likely to get many benefits from traditional chemotherapy. Over-expression of BCL-2 family proteins is tightly correlated with progression of pheochromocytoma. ApoG2, as the most potent gossypol derivative, has exhibited anti-tumor activities in various tumors. In the present study, we found that the staining degree of Bcl-2 being stronger than Bax was more frequently observed in pheochromocytoma than adrenocorticohyperplasia, which was possibly related to shorter overall survival. In addition, ApoG2 could induce apoptosis through up-regulation of Bax and down-regulation of Bcl-2, increasing reactive oxygen species (ROS) levels, inducing cytochrome C release and cleaving caspase proteins. Most importantly, those inhibition effects were blocked by caspase activation inhibitor Z-VAD-fmk and antioxidant N-acetyl-L-cysteine. The above results were further confirmed in vivo. Furthermore, ApoG2 could effectively inhibit tumor movement capabilities. Altogether, our results indicated that ApoG2 was a potential effective target drug for pheochromocytoma.