PURPOSE: Although histone deacetylase inhibitors (HDACi) are emerging as a new 
class of anticancer agents, one of the most significant concerns is that 
interactions with a wide array of substrates using these agents might initiate 
both therapeutic and undesired protective responses. Here, we sought to identify 
the potential protective reactions initiated by HDACi and determine whether 
targeting these reactions would enhance the antitumoral activity of HDACi.
EXPERIMENTAL DESIGN: Gene expression profiles were analyzed by cDNA microarray 
in Molt-4 cells before and after treatment of vorinostat. Induction of CD146 by 
vorinostat was examined in a wide range of tumors and nonmalignant cells. AA98, 
an anti-CD146 monoclonal antibody, was used to target CD146 function. 
Synergistic antitumoral and antiangiogenic effects between AA98 and vorinostat 
were examined both in vitro and in vivo. The potential effect of combined AA98 
and vorinostat treatment on the AKT pathway was determined by Western blotting.
RESULTS: The induction of CD146 is a common phenomenon in vorinostat-treated 
cancer but not in nonmalignant cells. Targeting of CD146 with AA98 substantially 
enhanced vorinostat-induced killing via the suppression of activation of AKT 
pathways in cancer cells. Moreover, AA98 in combination with vorinostat 
significantly inhibited angiogenesis. In vivo, AA98 synergized with vorinostat 
to inhibit tumor growth and metastasis.
CONCLUSION: The present study provided the first evidence that an undesired 
induction of CD146 could serve as a protective response to offset the antitumor 
efficacy of vorinostat. On the other hand, targeting CD146 in combination with 
vorinostat could be exploited as a novel strategy to more effectively kill 
cancer cells.