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Gemcitabine and cisplatin (GC) has been widely used for advanced and metastatic urothelial carcinoma (UC). However, resistance to this remedy has been noticed. We have demonstrated that increase of TG-interacting factor (TGIF) in specimens is associated with worse prognosis of upper tract UC (UTUC) patients. The roles of TGIF in the gemcitabine resistance of UC were explored. Specimens of 23 locally advanced/advanced stage UTUC patients who received GC systemic chemotherapy after radical nephroureterectomy were collected to evaluate the alterations of TGIF in the resistance to the remedy by using immunohistochemistry. In vitro characterizations of mechanisms mediating TGIF in gemcitabine resistance were conducted by analyzing NTUB1 cells and their gemcitabine-resistant subline, NGR cells. Our results show that increased TGIF is significantly associated with chemo-resistance, poor progression-free survival, and higher cancer-related deaths of UTUC patients. Higher increases of TGIF, p-AKT Ser473 and invasive ability were demonstrated in NGR cells. Overexpression of TGIF in NTUB1 cells upregulated p-AKT Ser473 activation, enhanced migration ability, and attenuated cellular sensitivity to gemcitabine. Knockdown of TGIF in NGR cells downregulated p-AKT Ser473 activation, declined migration ability, and enhanced cellular sensitivity to gemcitabine. In addition, histone deacetylases inhibitor trichostatin A (TSA) inhibited TGIF, p-AKT Ser473 expression and migration ability. Synergistic effects of gemcitabine and TSA on NGR cells were also demonstrated. Collectively, TGIF contributes to the gemcitabine resistance of UC via AKT activation. Combined treatment with gemcitabine and TSA might be a promising therapeutic remedy to improve the gemcitabine resistance of UC. [ABSTRACT FROM AUTHOR]

Understanding how chemotherapeutic agents mediate testicular toxicity is crucial in light of compelling evidence that male infertility, one of the severe late side effects of intensive cancer treatment, occurs more often than they are expected to. Previous study demonstrated that bortezomib (BTZ), a 26S proteasome inhibitor used to treat refractory multiple myeloma (MM), exerts deleterious impacts on spermatogenesis in pubertal mice via unknown mechanisms. Here, we showed that intermittent treatment with BTZ resulted in fertility impairment in adult mice, evidenced by testicular atrophy, desquamation of immature germ cells and reduced caudal sperm storage. These deleterious effects may originate from the elevated apoptosis in distinct germ cells during the acute phase and the subsequent disruption of Sertoli–germ cell anchoring junctions (AJs) during the late recovery. Mechanistically, balance between AMP-activated protein kinase (AMPK) activation and Akt/ERK pathway appeared to be indispensable for AJ integrity during the late testicular recovery. Of particular interest, the upregulated testicular apoptosis and the following disturbance of Sertoli–germ cell interaction may both stem from the excessive oxidative stress elicited by BTZ exposure. We also provided the in vitro evidence that AMPK-dependent mechanisms counteract follicle-stimulating hormone (FSH) proliferative effects in BTZ-exposed Sertoli cells. Collectively, BTZ appeared to efficiently prevent germ cells from normal development via multiple mechanisms in adult mice. Employment of antioxidants and/or AMPK inhibitor may represent an attractive strategy of fertility preservation in male MM patients exposed to conventional BTZ therapy and warrants further investigation. [ABSTRACT FROM AUTHOR]

Abstract Background Selenium supplementation can be used to treat tumors. However, inorganic selenium is highly toxic, and natural organic selenium is extremely rare. Polysaccharides can improve drug bioavailability and targeting. Lentinan is a polysaccharide that has been approved as an anti-cancer drug in Japan and China. Methods Lentinan, an antitumor polysaccharide extracted from Lentinus edodes , was conjugated with seleninic acid to be transformed into ester (Se–lentinan) and utilized as drug carrier. The enhancement of the anti-tumor effects of Se–lentinan was evaluated by cell viability, cell cycle, migration, and transwell assays and animal xenograft models. The effects of Se-lentinan on the expression levels of epithelial–mesenchymal transition (EMT) markers were determined through immunofluorescence, Western blot, and immunohistochemistry analyses. Results Se–lentinan inhibited the invasiveness of B16-BL6 and HCT-8 cells by suppressing EMT. In vivo, Se–lentinan significantly inhibited tumor growth and metastasis of the transplanted melanoma and colon cancer cells and showed less toxicity than sodium selenite. Moreover, Se–lentinan reduced the accumulation of selenium in the liver and kidney tissues of mice and exhibited low organ toxicity. Conclusion The antitumor activity of selenium was enhanced greatly, and its side effects were reduced with the use of lentinan as drug carrier. Highlights • Lentinan was utilized as a drug carrier. • Se-lentinan inhibited the invasion abilities and growths of Melanoma. • Se-lentinan inhibited tumor growth and metastasis with less toxicity. • Se-lentinan reduced the accumulation of selenium in the tissues of mice. [ABSTRACT FROM AUTHOR]

Lysosomes are important targets for anticancer drug discovery. Our previous study showed that Riccardin D-N (RD-N), a natural macrocylic bisbibenzyl derivative produced by Mannich reaction, induced cell death by accumulating in lysosomes. Experiments were performed on human lung squamous cell carcinoma tissue from left inferior lobar bronchus of patient xenografts and H460 cells. RD-N was administrated for 25 days. The specimens of xenografts in Balb/c athymic (nu +/nu +) male mice were removed for immunohistochemistry, subcellular fractionation, enzyme activities and Western blotting analysis. mRFP-GFP-LC3 reporter was used to examine autophagy in H460 cells. Sphingomyelin assay was evaluated by thin-layer chromatography and assay kit. Lysosomal membrane permeabilization (LMP) caused by acid sphingomyelinase (ASM) inhibition and subsequent changes of sphingomyelin (SM) metabolism selectively destabilized the cancer cell lysosomes in RD-N-treated H460 cells in vitro and tumor xenograft model in vivo . The destabilized lysosomes induced the release of cathepsins from the lysosomes into the cytosol and further triggered cell death. These results explain the underlying mechanism of RD-N induced LMP. It can be concluded that a more lysosomotropic derivative was synthesized by introduction of an amine group, which could have more potential applications in cancer therapy. [ABSTRACT FROM AUTHOR]

Cigarette smoking, a major stroke risk factor, upregulates endothelin receptors in cerebral arteries. The present study examined the effects of MEK1/2 pathway inhibition on cigarette smoke exposure-induced ET receptor upregulation. Rats were exposed to the secondhand smoke (SHS) for 8 weeks followed by intraperitoneal injection of MEK1/2 inhibitor, U0126 for another 4 weeks. The urine cotinine levels were assessed with high-performance liquid chromatography. Contractile responses of isolated cerebral arteries were recorded by a sensitive wire myograph. The mRNA and protein expression levels of receptor and MEK/ERK1/2 pathway molecules were examined by real-time PCR and Western blotting, respectively. Cerebral artery receptor localization was determined with immunohistochemistry. The results showed the urine cotinine levels from SHS exposure group were significantly higher than those from the fresh group. In addition, the MEK1/2 inhibitor, U0126 significantly reduced SHS exposure-increased ET A receptor mRNA and protein levels as well as contractile responses mediated by ET A receptors. The immunoreactivity of increased ET A receptor expression was primarily cytoplasmic in smooth muscle cells. In contrast, ET B receptor was noted in endothelial cells. However, the SHS-induced decrease in endothelium-dependent relaxation was unchanged after U0126 treatment. Furthermore, SHS increased the phosphorylation of MEK1/2 and ERK1/2 protein in cerebral arteries. By using U0126 could inhibit the phosphorylated ERK1/2 protein but not MEK1/2. Taken together, our data show that treatment with MEK1/2 pathway inhibitor offsets SHS exposure-induced ET A receptor upregulation in rat cerebral arteries. [ABSTRACT FROM AUTHOR]

The implication of chaperonin containing T-complex protein-1 subunit 3 (CCT3) in carcinogenesis has been observed in a diverse malignancies. However, the relevance of CCT3 in non-small cell lung cancer (NSCLC) has not been well addressed. This research is dedicated to investigating the expression pattern and functional role of CCT3 in NSCLC. An elevation in CCT3 levels was observed in NSCLC tissue, which was linked to a reduced overall survival rate. The inhibition of CCT3 by shRNA-mediated gene silencing induced suppressive effects on the transformative phenotypes of NSCLC cells, including the inhibition of cell proliferation and invasion, and the induction of cell cycle arrest and apoptosis. Further investigation revealed that the silencing of CCT3 led to the suppression of Yes-associated protein 1 (YAP1), and decreased the expression of YAP1 target genes in NSCLC cells. The activation of YAP1 via forced expression of constitutively active YAP1 mutant reversed CCT3-restraint-evoked antitumor effects in NSCLC cells. Crucially, NSCLC cells with CCT3 silencing also exhibited weakened oncogenicity in nude mice associated with the down-regulation of YAP1 activation in xenografts. To sum up, these observations of our work show that the inhibition of CCT3 produces antitumor effects in NSCLC via the suppression of YAP1. This study unveils a possible role CCT3/YAP1 axis in NSCLC and suggests CCT3 as a candidate anticancer target. [Display omitted] • CCT3 is elevated in NSCLC and associated with poor prognosis. • Restraint of CCT3 has cancer-inhibiting effects in NSCLC. • CCT3 mediates the activation of YAP1. • CCT3 regulates NSCLC progression by YAP1 signaling. [ABSTRACT FROM AUTHOR]

Benzethonium chloride (BZT) and domiphen bromide (DMP) are widely used as antimicrobials in drugs, vaccines and industry. However, no cardiac safety data has been developed on both compounds. Previously we reported BZT and DMP as high-affinity human ether-a-go-go related gene (HERG) channel inhibitors with unknown proarrhythmic risk. Here, we investigate the cardiotoxicity of BZT and DMP in vitro and in vivo, aiming to improve the safety-in-use of both antimicrobials. In the present study, human iPSC derived cardiomyocytes (hiPSC-CMs) were generated and rabbit models were used to examine the proarrhythmic potential of BZT and DMP. Our results found that BZT and DMP induced time- and dose-dependent decrease in the contractile parameters of hiPSC-CMs, prolonged FPDc (≥ 0.1 μM), caused tachycardia/fibrillation-like oscillation (0.3–1 μM), ultimately progressing to irreversible arrest of beating (≥ 1 μM). The IC50 values of BZT and DMP derived from normalized beat rate were 0.13 μM and 0.10 μM on hiPSC-CMs at 76 days. Moreover, in vivo rabbit ECG data demonstrated that 12.85 mg/kg BZT and 3.85 mg/kg DMP evoked QTc prolongation, noncomplex arrhythmias and ventricular tachycardias. Our findings support the cardiac safety of 0.01 μM BZT/DMP in vitro and the intravenous infusion of 3.85 mg/kg BZT and 1.28 mg/kg DMP in vivo, whereas higher concentrations of both compounds cause mild to moderate cardiotoxicity that should not be neglected during medical and industrial applications. • Benzethonium chloride and domiphen bromide induce arrhythmia in vitro and in vivo. • Both compounds significantly prolong FPDc and QTc interval. • The inhibition of hiPSC-CMs by these two compounds is dose- and time-dependent. • Domiphen bromide is more toxic than benzethonium chloride in vivo. • Mild to moderate cardiotoxicity is proposed for these two compounds. [ABSTRACT FROM AUTHOR]

WHO suggests that colon cancer incidences are rising steadily, propelling researchers to search for novel chemotherapeutic options. Metal-based chemotherapy is a potential forte to explore ruthenium-based complexes, exhibiting the capability to influence a variety of cellular targets. We discovered the chemotherapeutic effects of ruthenium-rifampicin complex on HT-29 and HCT-116 human colorectal cell lines and on a chemically developed murine colorectal cancer model. Complex was synthesized and characterized by analytical techniques and evaluation of antioxidant potential along with DNA binding capabilities. The complex minimizes cellular propagation and initiates apoptotic events in the colon cancer cell lines of HT-29 and HCT-116. The results of the in vivo study suggest that the complex has been successful in minimizing the wide spectrum of aberrant crypt foci and hyperplastic lesions, as well as encouraging elevated amounts of CAT, SOD and glutathione. Along with that, p53 could be modulated by the ruthenium-rifampicin complex to interfere with apoptosis in colon carcinoma, initiated by the intrinsic apoptotic trail facilitated through Bcl2 and Bax, thus controlling the Akt/mTOR/VEGF pathway coupled through the WNT/β-catenin trail. Ruthenium-rifampicin chemotherapy could interrupt, retract or interrupt the progression of colorectal cancer through modifying intrinsic apoptosis including the antiangiogenic pathway, thereby achieving the function of a potential contender in chemotherapy in the near future. [Display omitted] • Synthesis of novel ruthenium rifampicin complex and their characterization • Chemotherapeutic efficacy of complex in colon cancer cells • Deciphering of signal transduction pathway of the complex in colon carcinoma • Evaluation of apoptotic events in colon carcinoma [ABSTRACT FROM AUTHOR]

Urothelial carcinoma (UC) is one of the highest incidence cancers that rank the fourth commonly diagnosed tumors worldwide. The unresectable lesions that are resistant to therapeutic interventions is the major cause leading to death. Previous studies had shown that the resistance and metastatic consequence may arise from cancer stem-like cells population. The phytochemical flavonoids have promised bioactivity and potent anti-carcinogenic effects, and trap great attentions for cancer chemoprevention and/or adjuvant chemotherapy. However, the mechanisms of flavonoids on cancer stemness is still obscured. In this study, we analyzed the biofunctional effects of as-prepared flavonoid derivative-WYC0209 on T24, BFTC905 and BFTC909 human UC cell lines. Our results demonstrated that WYC0209 significantly induced anti-cell viability on UC cells through decreased Akt/NFkB signaling. Moreover, WYC0209 enhanced the cell apoptosis through activated the caspase-3 activity and inactivated Bcl-xL expression. Interestingly, WYC0209 dramatically inhibited the cancer stem cells (CSCs) traits, including attenuation of side population and tumorsphere formation in which were through declined EMT-CSCs markers including MDR1, ABCG2 and BMI-1. We further validated the effects of WYC0209 on several CSC surface markers including CD133, CD44, SOX-2 and Nanog. Our results showed that WYC0209 markedly inhibited CD133 expressions in both transcriptional and translational levels. High expression levels of CD133 was also demonstrated in human upper tract UC specimens. In summary, our study showed that WYC0209 may potentially as an adjuvant agent to against CD133-driven UC CSCs and provide a beneficial strategy to against UC cancer therapeutics resistant. Unlabelled Image • WYC0209-mediated anti-proliferation and cell apoptosis in UC cell lines. • WYC0209 dramatically inhibited the side population and tumorsphere formation. • WYC0209 markedly inhibited the CD133 expressions in mRNA and protein levels. • Highly levels of both mRNA and protein of CD133 were found in UTUC specimens. [ABSTRACT FROM AUTHOR]