scholarly journals Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3933
Author(s):  
Shao-Chuan Wang ◽  
Ya-Chuan Chang ◽  
Min-You Wu ◽  
Chia-Ying Yu ◽  
Sung-Lang Chen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Survivin Expression ◽  
Tumor Burden ◽  
Intravesical Instillation ◽  
Tumor Formation ◽  
Therapeutic Effects ◽  
Antibody Arrays

Azacitidine, an inhibitor of DNA methylation, shows therapeutic effects against several malignancies by inducing apoptosis and inhibiting tumor cell proliferation. However, the anti-tumor effects of azacitidine on urinary bladder urothelial carcinoma (UBUC), especially following intravesical instillation (IVI), are not established. Here, UBUC cell lines were used to analyze the in vitro therapeutic effects of azacitidine. Potential signaling pathways were investigated by antibody arrays and Western blotting. The N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced rat UBUC model was used for in vivo quantitative analysis of tumor burden. Azacitidine significantly inhibited DNMT expression in UBUC cell lines and reduced cell viability and clonogenic activity, as determined by MTT and colony formation assays, while also inducing significant cytotoxic effects in the form of increased sub-G1 and Annexin V-PI populations (all p < 0.05). Antibody arrays confirmed the in vitro suppression of TNF-R1 and the induction of TRAIL-R2 and their downstream signaling molecules. TNF-R1 suppression reduced claspin and survivin expression, while TRAIL-R2 activation induced cytochrome C and caspase 3 expression. Rats with BBN-induced bladder cancer had a significantly reduced tumor burden and Ki67 index following IVI of azacitidine (p < 0.01). Our study provides evidence for a reduction in BBN-induced bladder cancer by IVI of azacitidine through alterations in the TRAIL-R2 and TNF-R1 signaling pathways. These findings might provide new insights for further clinical trials.

scholarly journals A novel phosphoramide compound, DCZ0805, shows potent anti-myeloma activity via the NF-κB pathway

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xuejie Gao ◽  
Bo Li ◽  
Anqi Ye ◽  
Houcai Wang ◽  
Yongsheng Xie ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tumor Burden ◽  
High Rate ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Therapeutic Effects ◽  
Xenograft Mouse Model

Abstract Background Multiple myeloma (MM) is a highly aggressive and incurable clonal plasma cell disease with a high rate of recurrence. Thus, the development of new therapies is urgently needed. DCZ0805, a novel compound synthesized from osalmide and pterostilbene, has few observed side effects. In the current study, we intend to investigate the therapeutic effects of DCZ0805 in MM cells and elucidate the molecular mechanism underlying its anti-myeloma activity. Methods We used the Cell Counting Kit-8 assay, immunofluorescence staining, cell cycle assessment, apoptosis assay, western blot analysis, dual-luciferase reporter assay and a tumor xenograft mouse model to investigate the effect of DCZ0805 treatment both in vivo and in vitro. Results The results showed that DCZ0805 treatment arrested the cell at the G0/G1 phase and suppressed MM cells survival by inducing apoptosis via extrinsic and intrinsic pathways. DCZ0805 suppressed the NF-κB signaling pathway activation, which may have contributed to the inhibition of cell proliferation. DCZ0805 treatment remarkably reduced the tumor burden in the immunocompromised xenograft mouse model, with no obvious toxicity observed. Conclusion The findings of this study indicate that DCZ0805 can serve as a novel therapeutic agent for the treatment of MM.

Modified Yukmijihwangtang Suppresses the Production of Proinflammatory Cytokines in the Intravesical Hydrochloric Acid-Induced Cystitis Rat Model via the NF-κB Pathway

2012 ◽  
Vol 40 (02) ◽  
pp. 321-334 ◽  
Author(s):  
Jeong-Won Lee ◽  
Sok Cheon Pak ◽  
Songhee Jeon ◽  
Dong-Il Kim
Keyword(s):  
Medicinal Plants ◽  
Rat Model ◽  
In Vitro Study ◽  
Intravesical Instillation ◽  
Bladder Function ◽  
No Production ◽  
Therapeutic Effects ◽  
T24 Cells ◽  
Injury Group

Yukmijihwangtang (YM), a boiled extract of medicinal plants, has been prescribed for patients with kidney dysfunction in Korea; however, the mechanism underlying its therapeutic effects has not been fully elucidated. This study was conducted to evaluate the beneficial effects on bladder function by using modified YM (M-YM), which included Ulmi radicis cortex in addition to the six traditional medicinal plants in YM. Bladder irritation of the rats was caused by intravesical instillation of HCl . The animals were divided into six groups: sham group, cystitis-injury group with no treatment, cystitis-injury group with prednisolone treatment (5 mg/kg), and cystitis-injury with M-YM treatment (100, 200 or 500 mg/kg groups). Whole bladders were collected at day eight after injury. Samples were analyzed by histological and immunological examinations. An in vitro study was performed to determine whether M-YM extracts inhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) production and I κ B phosphorylation in a human uroepithelial cell line of T24 cells. Administration of M-YM notably improved bladder histological changes, and suppressed IL-6/TNF α production and I κ B phosphorylation in a rat model of chronic cystitis. M-YM also inhibited LPS-induced NO production and I κ B phosphorylation in T24 cells. This study suggests that administration of M-YM might be an applicable therapeutic traditional medicine for the treatment of interstitial cystitis.

scholarly journals Tanshinone IIA Inhibits Osteosarcoma Growth through a Src Kinase-Dependent Mechanism

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Chao Hu ◽  
Xiaobin Zhu ◽  
Taogen Zhang ◽  
Zhouming Deng ◽  
Yuanlong Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Src Kinase ◽  
Akt Signaling ◽  
Cellular Level ◽  
Tanshinone Iia

Introduction. Osteosarcoma is a malignant tumor associated with high mortality rates due to the toxic side effects of current therapeutic methods. Tanshinone IIA can inhibit cell proliferation and promote apoptosis in vitro, but the exact mechanism is still unknown. The aims of this study are to explore the antiosteosarcoma effect of tanshinone IIA via Src kinase and demonstrate the mechanism of this effect. Materials and Methods. Osteosarcoma MG-63 and U2-OS cell lines were stable transfections with Src-shRNA. Then, the antiosteosarcoma effect of tanshinone IIA was tested in vitro. The protein expression levels of Src, p-Src, p-ERK1/2, and p-AKt were detected by Western blot and RT-PCR. CCK-8 assay and BrdU immunofluorescence assay were used to detect cell proliferation. Transwell assay, cell scratch assay, and flow cytometry were used to detect cell invasion, migration, and cell cycle. Tumor-bearing nude mice with osteosarcoma were constructed. The effect of tanshinone IIA was detected by tumor HE staining, tumor inhibition rate, incidence of lung metastasis, and X-ray. Results. The oncogene role of Src kinase in osteosarcoma is reflected in promoting cell proliferation, invasion, and migration and in inhibiting apoptosis. However, Src has different effects on cell proliferation, apoptosis, and cell cycle regulation among cell lines. At a cellular level, the antiosteosarcoma effect of tanshinone IIA is mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. At the animal level, tanshinone IIA played a role in resisting osteosarcoma formation by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways. Conclusion. Tanshinone IIA plays an antiosteosarcoma role in vitro and in vivo and inhibits the progression of osteosarcoma mediated by Src downstream of the MAPK/ERK and PI3K/AKt signaling pathways.

Synthesis, Characterization, and Biological Activity of Anthraquinone-Substituted Imidazolium Salts for the Treatment of Bladder Cancer

2020 ◽  
Vol 6 (4) ◽  
pp. 471-479
Author(s):  
Michael L. Stromyer ◽  
David J. Weader ◽  
Uttam Satyal ◽  
Philip H. Abbosh ◽  
Wiley J. Youngs
Keyword(s):  
Bladder Cancer ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
High Grade ◽  
Imidazolium Salts ◽  
Muscle Invasive Bladder Cancer ◽  
Imidazolium Salt ◽  
Muscle Invasive

BACKGROUND: Bladder cancer is one of the most common types of cancer diagnosed each year, and more than half of patients have non-muscle invasive bladder cancer (NMIBC). The standard of care for patients with high-grade NMIBC is Bacillus Calmette-Guerin (BCG). Unfortunately, multiple BCG shortages have limited access to this treatment. Available alternatives using intravesical administration of chemotherapy have some efficacy, but lack prospective validation and long-term outcomes. Development of novel intravesical therapies may provide more active alternatives to BCG for patients with high-grade NMIBC. OBJECTIVE: To develop an optimal imidazolium salt for the intravesical treatment of NMIBC and determine preliminary in vitro activity of anthraquinone-substituted imidazolium salts. METHODS: The development of the anthraquinone-substituted imidazolium salts was undertaken in an attempt to increase the potency of this class of compounds by incorporating the quinone functional group observed in the chemotherapeutics doxorubicin, valrubicin, and mitomycin. All compounds were characterized by 1H and 13C NMR spectroscopy and infrared spectroscopy. Furthermore, these imidazolium salts were tested for in vitro cytotoxicity by the Developmental Therapeutics Program (DTP) on the NCI-60 human tumor cell line screening. Additional in vitro testing was performed against diverse bladder cancer cell lines (RT112, TCCSUP, J82, and UMUC13) using CellTiter-Glo® assays and colony-forming assays. RESULTS: The NCI-60 cell line screening indicated that compound 7 had the highest activity and was concluded to be the optimal compound for further study. Using CellTiter-Glo® assays on bladder cancer cell lines, 50% growth inhibitory concentration (IC50) values were determined to range from 32–50μM after an exposure of 1 h, for compound 7. Further evaluation of the compound by colony-forming assays showed the complete inhibition of growth at 10 days post a 100μM dose of compound 7 for 1 h. CONCLUSIONS: The most active lipophilic anthraquinone imidazolium salt, compound 7, could be a viable treatment for non-muscle invasive bladder cancer as it exhibits a cell-killing effect at a 1 h time period and completely inhibits cancer regrowth in colony-forming assays.

scholarly journals The Vitamin E Derivative Gamma Tocotrienol Promotes Anti-Tumor Effects in Acute Myeloid Leukemia Cell Lines

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2808 ◽  
Author(s):  
Ghanem ◽  
Zouein ◽  
Mohamad ◽  
Hodroj ◽  
Haykal ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Vitamin E ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Apoptotic Cell ◽  
Leukemia Cell ◽  
Therapeutic Effects ◽  
Apoptotic Pathway ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a blood cancer characterized by the formation of faulty defective myelogenous cells with morphological heterogeneity and cytogenic aberrations leading to a loss of their function. In an attempt to find an effective and safe AML treatment, vitamin E derivatives, including tocopherols were considered as potential anti-tumor compounds. Recently, other isoforms of vitamin E, namely tocotrienols have been proposed as potential potent anti-cancerous agents, displaying promising therapeutic effects in different cancer types. In this study we evaluated the anti-cancerous effects of γ-tocotrienol, on AML cell lines in vitro. For this purpose, AML cell lines incubated with γ-tocotrienol were examined for their viability, cell cycle status, apoptotic cell death, DNA fragmentation, production of reactive oxygen species and expression of proapoptotic proteins. Our results showed that γ-tocotrienol exhibits time and dose-dependent anti-proliferative, pro-apoptotic and antioxidant effects on U937 and KG-1 cell lines, through the upregulation of proteins involved in the intrinsic apoptotic pathway.

scholarly journals Modulation of Calretinin Expression in Human Mesothelioma Cells Reveals the Implication of the FAK and Wnt Signaling Pathways in Conferring Chemoresistance towards Cisplatin

2019 ◽  
Vol 20 (21) ◽  
pp. 5391 ◽  
Author(s):  
Wörthmüller ◽  
Salicio ◽  
Oberson ◽  
Blum ◽  
Schwaller
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Expression System ◽  
Single Agent ◽  
Wnt Signaling Pathway ◽  
Tumor Formation ◽  
Mesenchymal Transition

Malignant mesothelioma (MM) is an aggressive asbestos-linked neoplasm, characterized by dysregulation of signaling pathways. Due to intrinsic or acquired chemoresistance, MM treatment options remain limited. Calretinin is a Ca2+-binding protein expressed during MM tumorigenesis that activates the FAK signaling pathway, promoting invasion and epithelial-to-mesenchymal transition. Constitutive calretinin downregulation decreases MM cells’ growth and survival, and impairs tumor formation in vivo. In order to evaluate early molecular events occurring during calretinin downregulation, we generated a tightly controlled IPTG-inducible expression system to modulate calretinin levels in vitro. Calretinin downregulation significantly reduced viability and proliferation of MM cells, attenuated FAK signaling and reduced the invasive phenotype of surviving cells. Importantly, surviving cells showed a higher resistance to cisplatin due to increased Wnt signaling. This resistance was abrogated by the Wnt signaling pathway inhibitor 3289-8625. In various MM cell lines and regardless of calretinin expression levels, blocking of FAK signaling activated the Wnt signaling pathway and vice versa. Thus, blocking both pathways had the strongest impact on MM cell proliferation and survival. Chemoresistance mechanisms in MM cells have resulted in a failure of single-agent therapies. Targeting of multiple components of key signaling pathways, including Wnt signaling, might be the future method-of-choice to treat MM.

scholarly journals The Antitumor Effect of Curcumin in Urothelial Cancer Cells Is Enhanced by Light Exposure In Vitro

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Frederik Roos ◽  
Katherina Binder ◽  
Jochen Rutz ◽  
Sebastian Maxeiner ◽  
August Bernd ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Bladder Cancer ◽  
Cell Growth ◽  
Visible Light ◽  
Cancer Cells ◽  
Cell Lines ◽  
Light Exposure ◽  
Bladder Cancer Cells

The natural compound curcumin exerts antitumor properties in vitro, but its clinical application is limited due to low bioavailability. Light exposure in skin and skin cancer cells has been shown to improve curcumin bioavailability; thus, the object of this investigation was to determine whether light exposure might also enhance curcumin efficacy in bladder cancer cell lines. RT112, UMUC3, and TCCSUP cells were preincubated with low curcumin concentrations (0.1-0.4μg/ml) and then exposed to 1.65 J/cm2visible light for 5 min. Cell growth, cell proliferation, apoptosis, cell cycle progression, and cell cycle regulating proteins along with acetylation of histone H3 and H4 were investigated. Though curcumin alone did not alter cell proliferation or apoptosis, tumor cell growth and proliferation were strongly blocked when curcumin was combined with visible light. Curcumin-light caused the bladder cancer cells to become arrested in different cell phases: G0/G1 for RT112, G2/M for TCCSUP, and G2/M- and S-phase for UMUC3. Proteins of the Cdk-cyclin axis were diminished in RT112 after application of 0.1 and 0.4μg/ml curcumin. Cell cycling proteins were upregulated in TCCSUP and UMUC3 in the presence of 0.1μg/ml curcumin-light but were partially downregulated with 0.4μg/ml curcumin. 0.4μg/ml (but not 0.1μg/ml) curcumin-light also evoked late apoptosis in TCCSUP and UMUC3 cells. H3 and H4 acetylation was found in UMUC3 cells treated with 0.4μg/ml curcumin alone or with 0.1μg/ml curcumin-light, pointing to an epigenetic mechanism. Light exposure enhanced the antitumor potential of curcumin on bladder cancer cells but by different molecular action modes in the different cell lines. Further studies are necessary to evaluate whether intravesical curcumin application, combined with visible light, might become an innovative tool in combating bladder cancer.

scholarly journals HBO Promotes the Differentiation of Neural Stem Cells via Interactions Between the Wnt3/β-Catenin and BMP2 Signaling Pathways

2019 ◽  
Vol 28 (12) ◽  
pp. 1686-1699 ◽  
Author(s):  
Chongfeng Chen ◽  
Yujia Yang ◽  
Yue Yao
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Signaling Pathways ◽  
System Development ◽  
Nervous System Development ◽  
Bmp Signaling ◽  
Nuclear Proteins ◽  
Therapeutic Effects ◽  
Morphogenetic Protein

Hyperbaric oxygen (HBO) therapy may promote neurological recovery from hypoxic-ischemic encephalopathy (HIE). However, the therapeutic effects of HBO and its associated mechanisms remain unknown. The canonical Wnt/β-catenin signaling pathways and bone morphogenetic protein (BMP) play important roles in mammalian nervous system development. The present study examined whether HBO stimulates the differentiation of neural stem cells (NSCs) and its effect on Wnt3/β-catenin and BMP2 signaling pathways. We showed HBO treatment (2 ATA, 60 min) promoted differentiation of NSCs into neurons and oligodendrocytes in vitro. In addition, rat hypoxic-ischemic brain damage (HIBD) tissue extracts also promoted the differentiation of NSCs into neurons and oligodendrocytes, with the advantage of reducing the number of astrocytes. These effects were most pronounced when these two were combined together. In addition, the expression of Wnt3a, BMP2, and β-catenin nuclear proteins were increased after HBO treatment. However, blockade of Wnt/β-catenin or BMP signaling inhibited NSC differentiation and reduced the expression of Wnt3a, BMP2, and β-catenin nuclear proteins. In conclusion, HBO promotes differentiation of NSCs into neurons and oligodendrocytes and reduced the number of astrocytes in vitro possibly through regulation of Wnt3/β-catenin and BMP2 signaling pathways. HBO may serve as a potential therapeutic strategy for treating HIE.

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