Effect of Trans-2,3-Dimethoxycinnamoyl Azide on Enhancing Antitumor Activity of Romidepsin on Human Bladder Cancer

Abstract

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.In the United States, transitional cell carcinoma (TCC) of bladder is estimated to affect 67,160 new cases, with 13,750 deaths in 2007 (1). Conventional cytotoxic chemotherapy (such as methotrexate, vinblastine, doxorubicin, and cipslatin) is commonly used as a main regimen for advanced stages of bladder cancer (2, 3). However, drug resistance due to tumor heterogeneity (4) and serious side effects from current treatment regimens have made outcome unsatisfactory. Thus, developing novel effective chemotherapeutic regimens with fewer side effects are definitely needed to decrease the morbidity and mortality of TCC.Epigenetic regulation refers as gene expression controlled by changing chromatin structure without altering the DNA sequence per se (5). These changes, including DNA methylation and histone modifications (such as acetylation), are potentially reversible. Overwhelming evidence (6 -8) indicate that altered epigenetic regulation is associated with cancer development. Thus, targeting epigenetic machinery with different inhibitors (9, 10) has become a new avenue of cancer therapy. Recently, we have shown a potent in vitro growth inhibitory effect of DNA hypomethylating agent (e.g., 5-azacytidine) and romidepsin on several human TCC cell lines (11). Using xenograft models, we concluded that romidepsin is a promising agent for human bladder cancer (11).It is well known that drug resistance often emerges from single-agent regimen; therefore, developing rationalized combination strategy with higher therapeutic efficacy and acceptable drug toxicit...

Tranilast inhibits hormone refractory prostate cancer cell proliferation and suppresses transforming growth factor β1‐associated osteoblastic changes

“…Tranilast may inhibit proliferation of prostate caner in bone metastasis meditated through suppression of IGF-1 secretion from the bone cortex as well as TGF-b1. Recently, Fan et al [40] reported that tranilast may be able to enhance the anti-tumor effect of romidepsin (FK228, depsipeptide), a unique cyclic depsipeptide with a histone deacetylase inhibitor activity, in bladder cancer cells. Tranilast may also become a useful chemical agent for combination therapy with chemotherapy or molecular targeting therapy.…”

Tranilast: A review of its therapeutic applications

“…Fan et al reported that tranilast might enhance the anti-tumor effects of romidepsin, which is a histone deacetylase inhibitor, in bladder cancer cells [96].…”

“…Moreover, tranilast in combination with adriamycin, cisplatin, vindesine, or cyclophosphamide, suppressed tumor growth and angiogenesis of lung carcinoma cells more powerfully than each agent alone [91]. It may be able to enhance the anti-tumor effects of romidepsin in bladder cancer cells [96]. The combination of tranilast with cyclosporine A (CsA) is a useful strategy to reduce the adverse effects of CsA, and this mixture efficiently inhibited acute liver rejection in a rat orthotopic liver transplantation model [39].…”

Structure-Activity Relationship Studies of β-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site

“…For example, trans -2,3-dimethoxycinnamoyl azide derivative 1 (Fig. 1A ) enhanced the in vitro and in vivo antitumor effect of romidepsin on bladder cancer cells 27 . The Combretastatin A-4 aryl azide analogue 2 (Fig.…”