A Histone Deacetylase Inhibitor, OBP-801, and Celecoxib Synergistically Inhibit the Cell Growth with Apoptosis via a DR5-Dependent Pathway in Bladder Cancer Cells

Abstract

The prognosis of muscle-invasive bladder cancer with metastasis is poor. There have been no therapeutic improvements for many years, and an innovative therapy for muscle-invasive bladder cancer has been awaited to replace the conventional cytotoxic chemotherapy. Here, we show a candidate method for the treatment of bladder cancer. The combined treatment with a novel histone deacetylase (HDAC) inhibitor, OBP-801, and celecoxib synergistically inhibited cell growth and markedly induced apoptosis through the caspase-dependent pathway in high-grade bladder cancer cells. Furthermore, the combined treatment induced expression of death receptor 5 (DR5). We identified that knockdown of DR5 by small interfering RNA (siRNA) significantly suppressed apoptosis by the combined treatment. Therefore, we conjectured that the apoptosis induced by OBP-801 and celecoxib is at least partially dependent on DR5. However, it was interesting that the combined treatment drastically suppressed expression of DR5 ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). These data suggest that there is no involvement of TRAIL in the induction of apoptosis by the combination, regardless of the dependence of DR5. Moreover, xenograft studies using human bladder cancer cells showed that the combined therapy suppressed tumor growth by upregulating expressions of DR5 and Bim. The inhibition of tumor growth was significantly more potent than that of each agent alone, without significant weight loss. This combination therapy provided a greater benefit than monotherapy in vitro and in vivo. These data show that the combination therapy with OBP-801 and celecoxib is a potential novel therapeutic strategy for patients with muscle-invasive bladder cancer. Mol Cancer Ther; 15(9); 2066-75. Ó2016 AACR.

The histone deacetylase inhibitor OBP-801 and eribulin synergistically inhibit the growth of triple-negative breast cancer cells with the suppression of survivin, Bcl-xL, and the MAPK pathway

“…We expected that OBP-801 known to suppress survivin [10,11] was an appropriate agent for the combination with eribulin when eribulin was proved to upregulate survivin in TNBC like other microtubule dynamics inhibitors [12]. Our findings showed that the combination treatment of OBP-801 and eribulin induced the synergistic growth inhibition of TNBC cells through apoptosis with the suppression of Bcl-xL and the MAPK pathway as well as survivin.…”

Celecoxib Inhibits Hepatocellular Carcinoma Cell Growth and Migration by Targeting PNO1

“…Celecoxib appears to inhibit multiple oncogenic targets and pathways depending on the cancer, including proliferation [24], apoptosis [25], angiogenesis [26], invasion [27], and tumor-induced immune suppression. Some of these pathways are dependent on COX-2, while others are independent of the enzyme [13,28].…”

FGFR inhibitor BGJ398 and HDAC inhibitor OBP-801 synergistically inhibit cell growth and induce apoptosis in bladder cancer cells

“…4). We previously reported that OBP-801 and celecoxib synergistically induced apoptosis via the DR5-dependent pathway, and that Bim partially acts as one of the key molecules downstream of DR5 in bladder cancer cells (17). Therefore, the DR5-dependent pathway may be partially involved in the caspase-dependent apoptosis by the combination of BGJ398 and OBP-801 in uM-uC-3 cells.…”

“…Western blotting. Western blot analysis was carried out as previously described (17). The following antibodies were purchased from the indicated sources: rabbit monoclonal antibodies for anti-Bim (ab32158) (Abcam, Cambridge, uK), anti-Bcl-xL (#2762), and anti-PARP (#9542) (Cell Signaling Technology, Beverly, MA, uSA); rabbit polyclonal antibodies for antisurvivin (AF886) (R&D Systems), anti-DR5 (#8074) (Cell Signaling Technology), anti-DR4 (1139) (ProSci, Inc., Poway, CA, uSA), anti-caspase-3 (#9665), anti-histone H4 (#2935), anti-acetyl-histone H4 (#9672), anti-Bid (#2002), anti-ERK1/2 (#9102), anti-Shp2 (#3752), anti-phospho ERK1/2 (#9101), anti-phospho FRS2-α (#3861), anti-phospho Shp2 (#3751) (Cell Signaling Technology), anti-FRS2-α (SC17841) (Santa Cruz Biotechnology, Dallas, TX, uSA); mouse monoclonal antibodies for anti-caspase-8 (M032-3) and anti-caspase-9 (M054-3) (MBL, Nagoya, Japan), anti-FLIP (ACX-804-961-0100) (Enzo Life Sciences, Farmingdale, NY, uSA), and anti-GAPDH (5G4) (HyTest, Ltd., Turku, Finland) were used as primary antibodies.…”