Abstract
BackgroundN-butylidenephthalide (BP) isolated from Radix Angelica Sinensis (Danggui) exhibits anti-tumorigenic effect in various cancer cells both in vivo and in vitro. The effect of BP in bladder cancer treatment is still unclear and worth for further investigate.MethodsChanges of patients with bladder cancer after Angelica Sinensis exposure were evaluated by analysis of Taiwan’s National Health Insurance Research Database (NHIRD) database. The anti-proliferative effect of BP on human bladder cancer cells was investigated and their cell cycle profiles after BP treatment were determined by flow cytometry. BP-induced apoptosis was demonstrated by Annexin V-FITC staining and TUNEL assay, while the expressions of apoptosis-related proteins were determined by western blot. The migration inhibitory effect of BP on human bladder cancer cells were shown by trans-well and wound healing assays. Tumor model in NOD-SCID mice were induced by injection of BFTC human bladder cancer cells.ResultsThe correlation of taking Angelica sinensis and the incidence of bladder cancer in NHIRD imply that this herbal product is worth for further investigation. BP caused bladder cancer cell death in a time- and dose- dependent manner and induced apoptosis via the activation of caspase-9 and caspase-3. BP also suppressed the migration of bladder cancer cells as revealed by the trans-well and wound healing assays. Up-regulation of E-cadherin and down-regulation of N-cadherin were evidenced by real-time RT-PCR analysis after BP treatment in vitro. Besides, in combination with BP, the sensitivity of these bladder cancer cells to cisplatin increased significantly. BP also suppressed BFTC xenograft tumor growth, and caused 44.2% reduction of tumor volume after treatment for 26 days.ConclusionsBP caused bladder cancer cell death through activation of mitochondria-intrinsic pathway. BP also suppressed the migration and invasion of these cells, probably by modulating EMT-related genes. Furthermore, combination therapy of BP with a lower dose of cisplatin significantly inhibited the growth of these bladder cancer cell lines. The incidence of bladder cancer decreased in patients who were exposed to Angelica sinensis, suggesting that BP could serve as a potential adjuvant in bladder cancer therapy regimen.
Highlights
N-butylidenephthalide (BP) isolated from Radix Angelica Sinensis (Danggui) exhibits anti-tumorigenic effect in various cancer cells both in vivo and in vitro
Platinum-based chemotherapy is commonly used for bladder cancer [5, 6], radical cystectomy and systemic chemotherapy are suggested for invasive bladder cancer
Since Taiwan’s National Health Insurance Research Database (NHIRD) has been successfully used in epidemiological studies of cancer and Chinese herbal products (CHPs) [14, 15], we investigated the correlation of taking Angelica sinensis and the incidence of bladder cancer in Taiwan
Summary
N-butylidenephthalide (BP) isolated from Radix Angelica Sinensis (Danggui) exhibits anti-tumorigenic effect in various cancer cells both in vivo and in vitro. Bladder cancer is one of the common cancer in the United States and many other parts of the world [1, 2]. The effect of chemotherapy or other systemic treatment for bladder cancer is limited [4]. Platinum-based chemotherapy is commonly used for bladder cancer [5, 6], radical cystectomy and systemic chemotherapy are suggested for invasive bladder cancer. These treatment regimens usually fail in 95% patients: at least half of the invasive bladder cancer patients still die of metastases within 2 years after diagnosis, and with less than 10% 5-year survival rate [2, 7]
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