Synergistic killing effect between vorinostat and target of CD146 in malignant cells.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Ma
Xiaoli
X
Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.
Liu
Jia
J
Wu
Jiang
J
Yan
Xiyun
X
Wu
Peng
P
Liu
Yong
Y
Li
Shuang
S
Tian
Yuan
Y
Cao
Yang
Y
Chen
Gang
G
Meng
Li
L
Xu
Gang
G
Wang
Shixuan
S
Lu
Yunping
Y
Ma
Ding
D
Zhou
Jianfeng
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D051929:CD146 Antigen / Q000276:immunology; D016923:Cell Death / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006367:HeLa Cells; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D000077337:Vorinostat; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D051929:CD146 Antigen; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C497902:MCAM protein, human; D000077337:Vorinostat