Abstract:Bladder cancer (BCa) represents the ninth most common malignancy worldwide. Despite intensive treatment with surgery and chemotherapy the prognosis for BCa patients particularly at advanced stages is poor. The ability to evade apoptosis is a hallmark of cancer cells. Since the antiapoptotic genes BCL2, Bcl-xL, XIAP and survivin are frequently upregulated in BCa tissues, their combined siRNA-mediated knockdown might be more potent in decreasing BCa growth than the single inhibition of one target. Against each t… Show more
“…Additionally, p53 has been previously indicated to transcriptionally activate Bax expression (25). The abnormal expression of the Bcl-2 and Bax proteins in bladder cancer has been previously illustrated (26,27). The results of the present study indicated an increased Bax/Bcl-2 ratio due to oxymatrine, which indicates that a p53-Bax dependent mechanism may be involved in this process.…”
Abstract.Oxymatrine has been shown to exert an antitumor effect on several types of cancer cells. However, the role of oxymatrine in bladder cancer has not yet been evaluated. The present study was designed to investigate the potential anti-proliferative effect of oxymatrine on bladder cancer T24 cells and the possible mechanisms involved. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine cell growth, and the cell morphology was examined using hematoxylin and eosin staining, wrights' staining and electron microscopy. The caspase-3 and survivin mRNA and protein levels were assessed using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The expression of tumor protein p53 (p53), Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) were analyzed using immunohistochemistry. Oxymatrine inhibited the proliferation of the T24 cells in a dose-and time-dependent manner. Oxymatrine also induced apoptosis and cell cycle arrest in the cells, in association with the upregulation of caspase-3 and Bax, and the downregulation of survivin, Bcl-2 and p53 expression. Overall, oxymatrine inhibits the proliferation of human bladder cancer cells by inducing apoptosis and cell cycle arrest via mechanisms that involve p53-Bax signaling and the downregulation of survivin expression.
IntroductionBladder cancer is one of the most common malignant tumors of the urinary system worldwide, affecting 16.6 per 100,000 males and 3.6 per 100,000 females (1). Although surgery is the usual and effective way to treat bladder cancer, the 5-year recurrence rate is ~50% following surgical treatment (2,3). At present, intravesical chemotherapy is the most frequently used method to prevent the recurrence of bladder cancer, subsequent to surgery (4). However, chemotherapy is often associated with multidrug resistance and toxic side effects, with little specificity to cancer cells, which elucidates the challenges of applying chemotherapy to bladder cancers. Natural compounds have previously emerged as a potential treatment for cancer therapy; therefore, natural compounds may be a promising target for bladder cancer therapy.Matrine, the active compound that may be extracted from the Chinese herb Sophora flavecens, has previously been used to treat chronic hepatitis B, allergic dermatitis and hypoleukocytosis, in China (5,6). Matrine may transform into oxymatrine, which may also be extracted from Sophora flavecens, and the nitrogen-oxygen bond may split under certain conditions transforming oxymatrine back to matrine (7). Several studies have demonstrated the multiple beneficial effects of matrine, including anti-arrhythmia (8), anti-inflammation (9,10) and anti-fibrosis (11,12) effects, with minimal side effects reported. In addition, previous studies have shown that matrine induces apoptosis in several cancer cell lines, including breast cancer MCF-7 cells (13) and pancreatic cancer PANC1 cells (14), using various mechanisms, which potentiate the role of...
“…Additionally, p53 has been previously indicated to transcriptionally activate Bax expression (25). The abnormal expression of the Bcl-2 and Bax proteins in bladder cancer has been previously illustrated (26,27). The results of the present study indicated an increased Bax/Bcl-2 ratio due to oxymatrine, which indicates that a p53-Bax dependent mechanism may be involved in this process.…”
Abstract.Oxymatrine has been shown to exert an antitumor effect on several types of cancer cells. However, the role of oxymatrine in bladder cancer has not yet been evaluated. The present study was designed to investigate the potential anti-proliferative effect of oxymatrine on bladder cancer T24 cells and the possible mechanisms involved. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine cell growth, and the cell morphology was examined using hematoxylin and eosin staining, wrights' staining and electron microscopy. The caspase-3 and survivin mRNA and protein levels were assessed using reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. The expression of tumor protein p53 (p53), Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) were analyzed using immunohistochemistry. Oxymatrine inhibited the proliferation of the T24 cells in a dose-and time-dependent manner. Oxymatrine also induced apoptosis and cell cycle arrest in the cells, in association with the upregulation of caspase-3 and Bax, and the downregulation of survivin, Bcl-2 and p53 expression. Overall, oxymatrine inhibits the proliferation of human bladder cancer cells by inducing apoptosis and cell cycle arrest via mechanisms that involve p53-Bax signaling and the downregulation of survivin expression.
IntroductionBladder cancer is one of the most common malignant tumors of the urinary system worldwide, affecting 16.6 per 100,000 males and 3.6 per 100,000 females (1). Although surgery is the usual and effective way to treat bladder cancer, the 5-year recurrence rate is ~50% following surgical treatment (2,3). At present, intravesical chemotherapy is the most frequently used method to prevent the recurrence of bladder cancer, subsequent to surgery (4). However, chemotherapy is often associated with multidrug resistance and toxic side effects, with little specificity to cancer cells, which elucidates the challenges of applying chemotherapy to bladder cancers. Natural compounds have previously emerged as a potential treatment for cancer therapy; therefore, natural compounds may be a promising target for bladder cancer therapy.Matrine, the active compound that may be extracted from the Chinese herb Sophora flavecens, has previously been used to treat chronic hepatitis B, allergic dermatitis and hypoleukocytosis, in China (5,6). Matrine may transform into oxymatrine, which may also be extracted from Sophora flavecens, and the nitrogen-oxygen bond may split under certain conditions transforming oxymatrine back to matrine (7). Several studies have demonstrated the multiple beneficial effects of matrine, including anti-arrhythmia (8), anti-inflammation (9,10) and anti-fibrosis (11,12) effects, with minimal side effects reported. In addition, previous studies have shown that matrine induces apoptosis in several cancer cell lines, including breast cancer MCF-7 cells (13) and pancreatic cancer PANC1 cells (14), using various mechanisms, which potentiate the role of...
“…54 by which that the maintenance of high p53 levels was deemed as a prerequisite for inducing cell apoptosis. However, this study could not be directed comparatively with that report as we had deliberately suppress three proteins in a simultaneous fashion although it is important to note that this was not the first time that this simultaneous repression of multiple protein target was attempted 55, 56 . Nonetheless the general consensus was that multiple protein suppression in a concurrent fashion could indeed shortened the time-line required for apoptosis (24 hours) 56–58 and our findings here were no different.Figure 5( A ) Levels of suppression of Survivin and expression of p53 for 2 h, 4 h and 8 h for MBA-MD 231 cells.…”
Measuring at ~30 nm, a fully customizable holliday junction DNA nanoconstruct, was designed to simultaneously carry three unmodified SiRNA strands for apoptosis gene knockout in cancer cells without any assistance from commercial transfection kits. In brief, a holliday junction structure was intelligently designed to present one arm with a cell targeting aptamer (AS1411) while the remaining three arms to carry different SiRNA strands by means of DNA/RNA duplex for inducing apoptosis in cancer cells. By carrying the three SiRNA strands (AKT, MDM2 and Survivin) into triple negative breast MDA-MB-231 cancer cells, cell number had reduced by up to ~82% within 24 hours solely from one single administration of 32 picomoles. In the immunoblotting studies, up-elevation of phosphorylated p53 was observed for more than 8 hours while the three genes of interest were suppressed by nearly half by the 4-hour mark upon administration. Furthermore, we were able to demonstrate high cell selectivity of the nanoconstruct and did not exhibit usual morphological stress induced from liposomal-based transfection agents. To the best of the authors’ knowledge, this system represents the first of its kind in current literature utilizing a short and highly customizable holliday DNA junction to carry SiRNA for apoptosis studies.
“…Inhibition of the Akt/NF-κB pathways results in the downregulation of Bcl-2 with a simultaneous upregulation of caspase-3 (20,22,25). In the present study, ursolic acid was used to treat T24 bladder cancer cells.…”
The Akt/NF-κB pathway is involved in numerous anti‑apoptotic and drug resistance events which occur in various types of bladder cancer. The present study investigated the role of ursolic acid in the regulation of anti-apoptotic Akt and NF-κBp65 signaling. T24 human bladder cancer cells were treated with ursolic acid at final concentrations of 12.5, 25 or 50 µmol/l for 48 h. Quantitative PCR (qPCR) and western blotting were performed to detect mRNA and protein expression, respectively. The results showed that anti-apoptotic phospho-Akt1 (pAkt1), phospho-IκBα (pIκBα), NF-κBp65 and Bcl-2 were inhibited and pro-apoptotic caspase-3 was upregulated in a dose‑dependent manner. A 50 µmol/l dose of ursonic acid decreased the mRNA expression levels of anti-apoptotic NF-κBp65 and Bcl-2 0.17 (8.9/52.6)-fold and 0.22 (9.5/42.3)‑fold, respectively. The pro-apoptotic caspase-3 mRNA expression levels were upregulated 4.78 (38.7/8.1)-fold. The anti-apoptotic pAkt1, pIκBα, NF-κBp65 and Bcl-2 protein levels were downregulated to 5.1 (blot grayscales vs. control at 32.3), 3.2 (vs. 24.2), 8.5 (vs. 45.1) and 9.2 (vs. 40.3). The protein levels of pro-apoptotic caspase-3 were upregulated to 20.7 (vs. 4.7). The proliferative activity of T24 cells treated with 12.5, 25.0 and 50.0 µmol/l ursolic acid was significantly reduced compared with that of control cells (83.8, 56.2 and 31.5 vs. 97.6%, respectively, P<0.05 for each). In conclusion, ursolic acid is important in inducing apoptosis via the suppression of Akt/NF-κB signaling in T24 human bladder cancer cells and this occurs in a dose-dependent manner. Ursolic acid may therefore serve as a naturally occurring candidate drug for the prevention and treatment of bladder cancer.
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