Synergistic antitumor effects of the combined treatment with an HDAC6 inhibitor and a COX-2 inhibitor through activation of PTEN.

Chemotherapy is one of the most effective non-surgical treatments for various types of tumor. Identifying different combinations of antitumor agents that can produce synergistic antitumor effects remains an important clinical strategy. In the present study, we showed that the combination of histone deacetylase 6 (HDAC6) inhibitor tubastatin A together with cyclooxygenase-2 (COX-2) inhibitor celecoxib resulted in synergistic antitumor effects in CAL 27 and SACC-83 cells. Treatment with celecoxib alone promoted the membrane translocation of phosphatase and tensin homolog (PTEN), indicating PTEN activation, and consequently led to protein kinase B (AKT) dephosphorylation (inactivation). Similarly, treatment with an HDAC6 inhibitor alone promoted PTEN membrane translocation and correspondingly dephosphorylated AKT. The combination of celecoxib and an HDAC6 inhibitor synergistically increased PTEN membrane translocation and inactivated AKT. Moreover, celecoxib enhanced the HDAC6 inhibitor-induced antitumor effects in PTEN-deficient U-87 MG cells that had been stably transfected with wild-type PTEN, but not in the same cell line stably transfected with mutant PTEN-K163R, which cannot be activated by HDAC6 inhibitors. In summary, the results indicated that the COX-2 inhibitor celecoxib enhanced the HDAC6 inhibitor-induced antitumor effects by activating the PTEN/AKT signaling pathway.