Effect of trans-2,3-dimethoxycinnamoyl azide on enhancing antitumor activity of romidepsin on human bladder cancer.
OBJECTIVE
Romidepsin (FK228, depsipeptide, FR901228), a unique cyclic depsipeptide with a histone deacetylase inhibitor (HDACI) activity, is a potential cancer therapeutic agent and currently under clinical trials for several types of cancer. For bladder cancer, romidepsin seems to be a potent antitumor agent from our recent study. In this study, we further delineate a new agent that can enhance both HDACI and antitumor activity of romidepsin.


METHODS
We screened a chemical library to identify candidate(s) that could enhance romidepsin activity. Chemical synthesis and purification were carried out to produce pure compound to examine its biochemical and antitumor effect on bladder cancer cell lines both in vitro and in vivo.


RESULTS
Tranilast, N-(acetoacetyl) anthranilic acid, was first identified as a lead compound from screening, and then, one of the analogues, 2,3-dimethoxycinnamoyl azide (DMCA), seems to be more potent than tranilast. Our data indicate that DMCA can potentiate the HDACI activity of romidepsin and other biological activities, such as cell cycle arrest and apoptosis; these effects were accompanied with the expression of various key cell cycle regulators in different bladder cancer cells. Consistently, DMCA can enhance the in vivo antitumor effect of romidepsin without causing any more weight loss than romidepsin alone.


CONCLUSIONS
DMCA is able to enhance the antitumor effect of romidepsin on bladder cancer from in vitro and in vivo.
Fan
Jinhai
J
Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9110, USA.
Stanfield
Jennifer
J
Guo
Yi
Y
Karam
Jose A
JA
Frenkel
Eugene
E
Sun
Xiankai
X
Hsieh
Jer-Tsong
JT
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001386:Azides / Q000008:administration & dosage*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation; D002934:Cinnamates / Q000008:administration & dosage*; D047630:Depsipeptides / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays; D062367:ortho-Aminobenzoates / Q000737:chemistry
C529262:2,3-dimethoxycinnamoyl azide; D001386:Azides; D002934:Cinnamates; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D062367:ortho-Aminobenzoates; C087123:romidepsin; D006655:Histone Deacetylases; C012293:tranilast