Abstract
Angiogenesis is a vital step during the process of oncogenesis of a lot of tumors, with no exception in bladder cancer. One of the useful strategies for the development of new drugs against cancer is targeting angiogenesis. In the present study, we found that a small-molecule natural product, which belonged to the β-carboline alkaloid, named harmine, could strongly inhibit tumor angiogenesis thus exhibiting its ideal treatment efficacy in bladder cancer. In vivo study verified that harmine had the effect of inhibition on human bladder tumor xenograft growth. The inhibitory effect of harmine to bladder cancer growth was coordinated by the effects shown on angiogenesis. To further explore the pharmacological activities of harmine, we tested harmine’s influence on blood vessel formation and found that harmine effectively blocked the microvessel sprouting in rat aortic ring assay when stimulated by vascular endothelial growth factor (VEGF). Furthermore, harmine inhibited human umbilical vein endothelial cell (HUVEC) proliferation as well as chemotactic motility, and when we treated HUVEC cell with harmine, the formation of capillary-like structures was also restrained. Moreover, harmine induced bladder cancer cell apoptosis through triggering the caspase-dependent apoptotic pathway and the downstream vascular endothelial growth factor receptor 2 (VEGFR2) kinase pathway was down-regulated, thus suppressing tumor development signals. Herein, our study demonstrated that natural product harmine might have potential in curing human bladder tumor because of its pharmacological function on tumor angiogenesis, trigged by VEGFR2 signaling pathways.
Highlights
The most common malignant tumor in the urinary system is bladder cancer which has a significant morbidity and mortality [1]
We wondered about the mechanism of harmine-inhibited tumor growth, we used a vascular endothelial growth factor receptor 2 (VEGFR2) antibody to stain solid tumor sections to test if this inhibition has some relationship with tumor angiogenesis
As shown by the IHC results, the average number of positive p-VEGFR2 in harmine-treated group was significantly decreased compared with untreated group (Figure 1C,D), suggesting that harmine might inhibit tumor growth partially due to its inhibition on tumor angiogenesis
Summary
The most common malignant tumor in the urinary system is bladder cancer which has a significant morbidity and mortality [1]. In today’s world, almost more than 380000 new cases are being diagnosed as bladder cancer every year, which amounts to the first incidence of whole urinary diseases [2]. In China, bladder cancer accounts for the eighth rank of all cancer-related mortalities. There is a relative lower incidence in China than in the western society, it is still in the face of great difficulties to cure bladder cancer. Benefiting from radical cystectomy and chemotherapy, approximately 35% of the patients suffering from local bladder cancer can survive above 5 years. The survival rate for those patients with distant metastatic bladder cancer is only about 6% [3]. It is extremely urgent to improve the therapeutic effect of bladder tumor
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