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Drug resistance is the predominant cause of mortality in late-stage patients with ovarian cancer. Histone deacetylase inhibitors (HDACis) have emerged as a novel type of second line drug with high specificity for tumor cells, including ovarian cancer cells. However, HDACis usually exhibit relatively low potencies when used as a single agent. The majority of current clinical trials are combination strategies. These strategies are more empirical than mechanism-based applications. Previously, it was reported that the adhesion molecule cluster of differentiation 146 (CD146) is significantly induced in HDACi-treated tumor cells. The present study additionally confirmed that the induction of CD146 is a common phenomenon in vorinostat-treated ovarian cancer cells. AA98, an anti-CD146 monoclonal antibody (mAb), was used to target CD146 function. Synergistic antitumoral effects between AA98 and vorinostat were examined in vitro and in vivo. The potential effect of combined AA98 and vorinostat treatment on the protein kinase B (Akt) pathway was determined by western blotting. The present study found that targeting of CD146 substantially enhanced vorinostat-induced killing via the suppression of activation of Akt pathways in ovarian cancer cells. AA98 in combination with vorinostat significantly inhibited cell proliferation and increased apoptosis. In vivo, AA98 synergized with vorinostat to inhibit tumor growth and prolong survival in ovarian cancer. These data suggest that an undesired induction of CD146 may serve as a protective response to offset the antitumor efficacy of vorinostat. By contrast, targeting CD146 in combination with vorinostat may be exploited as a novel strategy to more effectively kill ovarian cancer cells.