Abstract
Among challenges of targeted therapies is the activation of alternative pro-survival signaling pathways in cancer cells, resulting in an acquired drug resistance. Cyclooxygenase-2 (COX-2) is overexpressed in bladder cancer cells, making it an attractive molecular target for the detection and treatment of cancer. Fluorocoxib A is an optical imaging agent that selectively targets COX-2. In this study, we evaluated the ability of fluorocoxib A to monitor the responses of bladder cancer to targeted therapies in vivo. The effects of several tyrosine kinase inhibitors (TKIs: axitinib, AB1010, toceranib, imatinib, erlotinib, gefitinib, imatinib, sorafenib, vandetanib, SP600125, UO126, and AZD 5438) on COX-2 expression were validated in ten human and canine bladder cancer cell lines (J82, RT4, T24, UM-UC-3, 5637, SW780, TCCSUP, K9TCC#1Lillie, K9TCC#2Dakota, K9TCC#5Lilly) in vitro. The effects of TKIs on bladder cancer in vivo were evaluated using the COX-2-expressing K9TCC#5Lilly xenograft mouse model and detected by fluorocoxib A. The increased COX-2 expression was detected by all tested TKIs in at least one of the tested COX-2-expressing bladder cancer cell lines (5637, SW780, TCCSUP, K9TCC#1Lillie, K9TCC#2Dakota, and K9TCC#5Lilly) in vitro. In addition, fluorocoxib A uptake correlated with the AB1010- and imatinib-induced COX-2 expression in the K9TCC#5Lilly xenografts in vivo. In conclusion, these results indicate that fluorocoxib A could be used for the monitoring the early responses to targeted therapies in COX-2-expressing bladder cancer.
Highlights
Bladder cancer is the 6th most common type of cancer in the United States and one of the most expensive malignancies to treat due to high recurrence rates and lack of improved treatment options over the past several decades [1,2,3]
Our previously published studies demonstrated that treatments with RTKIs increase COX-2 expression in oral squamous cell carcinoma [32] and bladder cancer [29] cells in vitro
We further investigated the effect of two RTKIs, AB1010 and imatinib, in four COX-2-expressing bladder cancer cell lines (5637, TCCSUP, K9TCC#1Lillie, and K9TCC#5Lilly)
Summary
Bladder cancer is the 6th most common type of cancer in the United States and one of the most expensive malignancies to treat due to high recurrence rates and lack of improved treatment options over the past several decades [1,2,3]. In 90% of all cases, bladder cancer originates from the epithelial lining of the bladder known as the urothelium. This type of bladder cancer is known as the transitional cell carcinoma (TCC) or urothelial carcinoma [4]. Despite demonstrating the need for improved diagnostic screening, prevention, and treatment options, bladder cancer still remains one of the most commonly diagnosed malignancies in the United www.oncotarget.com. This drives the need for improved detection and novel therapeutic options for patients diagnosed with both non-muscle invasive bladder cancer and muscle invasive bladder cancer
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