TY - JOUR
T1 - Effect of Trans-2,3-dimethoxycinnamoyl azide on enhancing antitumor activity of romidepsin on human bladder cancer
AU - Fan, Jinhai
AU - Stanfield, Jennifer
AU - Guo, Yi
AU - Karam, Jose A.
AU - Frenkel, Eugene
AU - Sun, Xiankai
AU - Hsieh, Jer Tsong
PY - 2008/2/15
Y1 - 2008/2/15
N2 - Purpose: 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. Experimental Design: 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. Conclusion: DMCA is able to enhance the antitumor effect of romidepsin on bladder cancer from in vitro and in vivo.
AB - Purpose: 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. Experimental Design: 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. Conclusion: DMCA is able to enhance the antitumor effect of romidepsin on bladder cancer from in vitro and in vivo.
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U2 - 10.1158/1078-0432.CCR-07-1656
DO - 10.1158/1078-0432.CCR-07-1656
M3 - Article
C2 - 18281555
AN - SCOPUS:39749131015
SN - 1078-0432
VL - 14
SP - 1200
EP - 1207
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -