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HSP70 inhibitor VER155008 suppresses pheochromocytoma cell and xenograft growth by inhibition of PI3K/AKT/mTOR and MEK/ERK pathways.

According to the most recent World Health Organization classification, all pheochromocytomas have metastatic potential. Up until now there has been an absence of effective therapeutic methods to inhibit tumor growth and metastasis, especially in metastatic foci. Therefore, the discovery of new and effective drugs is urgently needed. Because overexpression of HSP70 frequently occurs in a variety of tumor tissues, VER155008, a new inhibitor targeting HSP70, has shown an anti-tumor effect through inhibition of PI3K/AKT/mTOR and MEK/ERK pathways, both of which are closely connected with pheochromocytoma proliferation, migration, and biologic behaviors. In our research, we reveal that VER155008 can reduce proliferation of the pheochromocytoma cell line PC12 and induce apoptosis at a relatively low dose. Most importantly, VER155008 can effectively suppress cell migration and invasion. Subsequently, drug-effect mechanisms of VER155008 were further detected by western blot, and we found that VER155008 exhibited an anti-tumor effect through down-regulating phosphorylation of the PI3K/AKT/mTOR and MEK/ERK signaling pathways. Finally, the above phenomena were further confirmed in a mouse model in vivo, and the results showed that the drug significantly inhibited xenograft tumor growth. In summary, VER155008 is a potential and promising effective drug for treating patients with pheochromocytoma, and furthermore, it could delay/inhibit tumor metastasis.