Adult ; Body Temperature/drug effects* ; COVID-19/pathology* ; Drug Therapy, Combination ; Drugs, Chinese Herbal/therapeutic use* ; Ephedra sinica/chemistry* ; Female ; Fever/pathology* ; Glycyrrhiza/chemistry* ; Humans ; Indoles/administration & dosage* ; Male ; Medicine, Chinese Traditional/methods* ; Middle Aged ; Phytotherapy/methods* ; Pneumonia, Viral/pathology* ; Radiography, Thoracic ; SARS-CoV-2/drug effects*

OBJECTIVETo explore the antitumoral effect of indirubin on androgen-independent prostate cancer PC-3 cells and its possible mechanisms.

METHODSWe measured the inhibitory effect of indirubin on the proliferation of prostate cancer PC-3 cells using MTT assay, detected their cell cycles by flow cytometry, and determined the expressions of the cell cycle regulatory protein cyclin D1 and its related downstream gene c-myc by Western blot.

RESULTSThe viability of the PC-3 cells was significantly decreased by indirubin in a concentration-dependent manner, reduced to 52. 2% and 13. 6% at 5 and 10 µmol/L, respectively. The cell cycle of the PC-3 cells was markedly inhibited by indirubin at 5 µmol/L, with the cells remarkably increased in the G0 and G1 phases and decreased in the S and G2/M phases. Meanwhile, indirubin also inhibited the expressions of cyclin D1 and c-myc in the Wnt signaling pathway.

CONCLUSIONIndirubin can suppress the proliferation of androgen-independent prostate cancer PC-3 cells, which may be associated with its inhibitory effect on the cell cycle and Wnt signaling pathway.

Antibiotics, Antineoplastic ; administration & dosage ; pharmacology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Coloring Agents ; Cyclin D1 ; metabolism ; Dose-Response Relationship, Drug ; Genes, myc ; Humans ; Indoles ; administration & dosage ; pharmacology ; Male ; Prostatic Neoplasms, Castration-Resistant ; drug therapy ; pathology ; Proto-Oncogene Proteins c-myc ; metabolism ; Tetrazolium Salts ; Thiazoles

OBJECTIVETo investigate the efficacy and safety of sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) on a 2 weeks on/1 week off intermittent dosing schedule.

METHODSA total of 11 mRCC patients were enrolled to receive sunitinib 50 mg/day in 2 weeks on/1 week off schedule per 6 weeks till disease progression or intolerable toxicity occurred. The primary end point was progression free survival (PFS), the secondary end points were overall survival (OS), incidence of adverse effects and objective response.

RESULTSThe objective response rate in the 11 cases was 45.5% and disease control rate 72.7% (partial response n = 5, stable disease n = 3). Till the last follow up on Dec 2013, the median PFS was 17.0 months (95% CI 7.3 to 26.7 months), and median OS 26.0 months (95% CI 2.2 to 49.8 months). The common adverse events included leucopenia, thrombocytopenia, diarrhea, mucositis and hand-foot skin reaction. Dose reduction to 37.5 mg was seen only in 2 patients without discontinuation.

CONCLUSIONSSunitinib on an intermittent dosing schedule 2 weeks on /1 week off as first-line therapy for mRCC patients shows a good efficacy and tolerance, with less grade 3-4 drug-related toxicities and a tendency of prolonged PFS in mRCC patients.

Antineoplastic Agents ; administration & dosage ; pharmacology ; therapeutic use ; Carcinoma, Renal Cell ; drug therapy ; Disease-Free Survival ; Drug Administration Schedule ; Humans ; Indoles ; administration & dosage ; pharmacology ; therapeutic use ; Kidney Neoplasms ; drug therapy ; Pilot Projects ; Pyrroles ; administration & dosage ; pharmacology ; therapeutic use ; Treatment Outcome

Sunitinib as a multitarget tyrosine kinase inhibitor is one of the anti-tumor agents, approved by the United States Food and Drug Administration to use treat gastrointestinal stromal tumor and metastatic renal cell carcinoma. The agent is known to commonly induce adverse reactions such as fatigue, nausea, diarrhea, stomatitis, esophagitis, hypertension, skin toxicity, reduciton in cardiac output of left ventricle, and hypothyroidism. However, it has been reported to rarely induce adverse reactions such as nephrotic syndrome and irreversible reduction in renal functions, and cases of intestinal perforation or pneumatosis interstinalis as such reactions have been consistently reported. In this report, a 66-year old man showing abdominal pain had renal cell carcinoma and history of sunitinib at a dosage of 50 mg/day on a 4-weeks-on, 2-weeks-off schedule. Seven days after the third cycle he was referred to the hospital because of abdominal pain. Computed tomography showed pneumoperitoneum with linear pneumatosis intestinalis in his small bowel. The patient underwent surgical exploration that confirmed the pneumatosis intestinalis at 100 cm distal to Treitz's ligament. We report a rare case of intestinal perforation with pneumatosis intestinalis after administration of sunitinib to a patient with metastatic renal cell carcinoma.
Aged ; Antineoplastic Agents/adverse effects/*therapeutic use ; Carcinoma, Renal Cell/*drug therapy ; Drug Administration Schedule ; Humans ; Indoles/adverse effects/*therapeutic use ; Intestinal Perforation/*diagnosis/etiology/surgery ; Kidney Neoplasms/*drug therapy ; Lung/radiography ; Male ; Pneumatosis Cystoides Intestinalis/*diagnosis/etiology ; Positron-Emission Tomography ; Pyrroles/adverse effects/*therapeutic use ; Tomography, X-Ray Computed

OBJECTIVETo investigate the therapeutic efficacy of double-mutated oncolytic adenovirus AxdAdB-3 in combination with gemcitabine for treating bladder cancer in an orthotopic nude mouse model.

METHODSThe susceptibility to the adenovirus was evaluated in bladder cancer cell lines YTS-1, T24, 5637 and KK47, and normal cell lines HCV29 and WI38. The cells were infected with AxCAlacZ and stained with 5-bromo-4-chloro-3-indolyl-β-galactoside (X-Gal). Immunostaining against adenoviral hexon protein was performed to determine the selective replication of AxdAdB-3 in the cancer cells. Flow cytometry was used to determine the YTS-1 cells in S phase of cell cycle after adenovirus infection. Cell viability after AxdAdB-3 and/or gemcitabine was measured by CCK-8 assay. Orthotopic bladder cancer model was established in nude mice, and the inhibitory efficacy of intravesical instillation therapy with AxdAdB-3 or/and gemcitabine was assessed.

RESULTSGene transduction efficiency was different among the cell lines, and correlated with expression of CAR. 5637 and KK47 cells with high expression of CAR were more susceptible to the adenovirus, whereas YTS-1 and T24 cells with little CAR expression were resistant to adenoviral infection. Immunostaining showed that the expression levels of hexon protein varied among the cell lines. Normal cells infected with AxdAdB-3 expressed little hexon protein. The proportion of S-phase cells was (39 ± 3) % and (49 ± 5) % in the AxCAlacZ- and AxdAdB-3-infected bladder cancer cells, respectively. AxdAdB-3 effectively induced S-phase entry of cell cycle (P < 0.05). AxdAdB-3 combined with gemcitabine significantly inhibited the growth of bladder cancer cell lines. In vivo, the mean weight of the bladder tumors in mice treated with intravesical instillation of AxCAlacZ, gemcitabine, AxdAdB-3, and AxdAdB-3 + gemcitabine were 400.6, 126.4, 82. 0, 40.4 mg, respectively. Either AxdAdB-3 (P < 0.0001) and gemcitabine (P < 0.0001) suppressed the tumor growth in nude mice, and the combination therapy reduced tumors more effectively than either AxdAdB-3 (P < 0.0001) or gemcitabine (P < 0.0001) alone.

CONCLUSIONSIntravesical instillation therapy with AxdAdB-3 in combination with gemcitabine can effectively inhibit the orthotopic bladder cancer in nude mouse, and further relevant clinical studies are guaranteed.

Adenoviridae ; genetics ; Administration, Intravesical ; Animals ; Antimetabolites, Antineoplastic ; administration & dosage ; pharmacology ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; pharmacology ; therapeutic use ; Deoxycytidine ; administration & dosage ; analogs & derivatives ; pharmacology ; therapeutic use ; Galactosides ; Indoles ; Mice ; Mice, Nude ; Models, Animal ; Urinary Bladder Neoplasms ; drug therapy

This study is to explore the interventional effects of fluvastatin on anti-beta2GPI/beta2GPI-induced activation in THP-1 mononuclear cells. In vitro, human mononuclear cells THP-1 were treated with fluvastatin, LPS and anti-beta2GPI/beta2GPI, then the TF expression on THP-1 cells was detected by real-time quantitative PCR (RT-qPCR) or TF activity was detected by kit. TNF-alpha mRNA and its protein expression were investigated by RT-PCR and ELISA kit. The expression of phospho-NF-kappaB p65 and inhibitory protein of NF-kappaB (IkappaB-alpha) were measured by Western blotting. The results suggested that the expression of TF and TNF-alpha on THP-1 cells was significantly up-regulated with treatment of anti-beta2GPI/beta2GPI complex (100 mg x L(-1)), compared with that of untreated cells (P < 0.05). Fluvastatin (50 mg x L(-1)) could decrease TF (mRNA and activity) expression and the level of TNF-alpha (mRNA and protein) in THP-1 cells with anti-beta2GPI/beta2GPI complex. The expression of TF and TNF-alpha was shown in a concentration-dependent manner. Moreover, anti-beta2GPI/beta2GPI complex could downregulate IkappaB-alpha levels and increase the levels of phospho-NF-kappaB p65. And these effects of anti-beta2GPI/beta2GPI complex could be blocked by fluvastatin. In conclusion, fluvastatin may interfere the expression and regulation of NF-kappaB signal transduction pathway, thereby inhibit the effects of anti-beta2GPI/beta2GPI on activation of THP-1 cells, by decreasing the expression of TF and TNF-alpha.
Antigen-Antibody Complex ; pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Fatty Acids, Monounsaturated ; administration & dosage ; pharmacology ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; administration & dosage ; pharmacology ; I-kappa B Proteins ; metabolism ; Indoles ; administration & dosage ; pharmacology ; Monocytes ; cytology ; metabolism ; NF-KappaB Inhibitor alpha ; Phosphorylation ; RNA, Messenger ; metabolism ; Signal Transduction ; drug effects ; Thromboplastin ; genetics ; metabolism ; Transcription Factor RelA ; metabolism ; Tumor Necrosis Factor-alpha ; genetics ; metabolism ; beta 2-Glycoprotein I ; antagonists & inhibitors ; immunology

OBJECTIVETo study the effect of histone deacetylase inhibitors trichostatin A (TSA) and LBH589 on the growth of human renal cell carcinoma OS-RC-2 cells in vitro and explore the underlying molecular mechanism.

METHODSOS-RC-2 cells were treated with LBH589 or TSA with or without SP600125 pretreatment, and the cell viability was measured by MTT assay. The changes of cell cycle distribution and apoptosis of OS-RC-2 cells were examined by flow cytometry, and the expressions of c-Jun, p-c-Jun, Bcl-2, and Bax were quantified by Western blotting.

RESULTSTSA and LBH589 both inhibited the growth of OS-RC-2 cells in a dose- and time-dependent manner. TSA at 1 µnmol/L and LBH589 at 50 nmol/L caused obvious cell cycle arrest in G2/M phase and cell apoptosis, and significantly increased the protein levels of phosphorylated c-Jun. TSA treatment obviously increased Bax expression but decreased Bcl2 expression in the cells. The growth inhibitory effect of TSA was attenuated by the JNK inhibitor SP600125 in OS-RC-2 cells. TSA-induced phosphorylation of c-Jun and Bax upregulation was partially counteracted by SP600125.

CONCLUSIONTSA and LBH589 can cause cell cycle arrest and induce apoptosis in OS-RC-2 cells, in which process P-JNK pathway plays an important role.

Anthracenes ; pharmacology ; Antineoplastic Agents ; administration & dosage ; pharmacology ; Apoptosis ; drug effects ; Carcinoma, Renal Cell ; metabolism ; pathology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Survival ; Dose-Response Relationship, Drug ; Histone Deacetylase Inhibitors ; administration & dosage ; pharmacology ; Humans ; Hydroxamic Acids ; administration & dosage ; pharmacology ; Indoles ; administration & dosage ; pharmacology ; JNK Mitogen-Activated Protein Kinases ; metabolism ; Kidney Neoplasms ; metabolism ; pathology ; MAP Kinase Signaling System ; drug effects ; Phosphorylation ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; bcl-2-Associated X Protein ; metabolism

PURPOSE: Postoperative ileus (POI) is an impairment of coordinated gastrointestinal (GI) motility that develops as a consequence of abdominal surgery and is a major factor contributing to patient morbidity and prolonged hospitalization. The aim of this study was to investigate the effects of different 5-hydroxytryptamine 4 (5-HT4) receptor agonists, which stimulate excitatory pathways, on a POI model. MATERIALS AND METHODS: The experimental model of POI in guinea pigs was created by laparotomy, gentle manipulation of the cecum for 60 seconds, and closure by suture, all under anesthesia. Different degrees of restoration of GI transit were measured by the migration of charcoal. Colonic transit was indirectly assessed via measurement of fecal pellet output every hour for 5 hours after administration of various doses of mosapride, tegaserod, prucalopride, and 5-HT. RESULTS: Charcoal transit assay showed that various 5-HT4 receptor agonists can accelerate delayed upper GI transit in a dose-dependent manner. However, fecal pellet output assay suggested that only prucalopride had a significant effect in accelerating colonic motility in POI. CONCLUSION: Although mosapride, tegaserod, and prucalopride produce beneficial effects to hasten upper GI transit in the POI model, prucalopride administered orally restores lower GI transit as well as upper GI transit after operation in a conscious guinea pig. This drug may serve as a useful candidate for examination in a clinical trial for POI.
Administration, Oral ; Animals ; Benzamides/pharmacology ; Benzofurans/administration & dosage/*pharmacology ; Charcoal/pharmacokinetics ; Colon/drug effects ; Dose-Response Relationship, Drug ; Gastrointestinal Motility/*drug effects ; Guinea Pigs ; Ileus/*surgery ; Indoles/pharmacology ; Laparotomy ; Male ; Morpholines/pharmacology ; Postoperative Complications/drug therapy ; Serotonin/pharmacology ; Serotonin 5-HT4 Receptor Agonists/*pharmacology

BACKGROUNDSunitinib has been proved an effective new option for treatment of metastatic renal cell carcinoma (mRCC). Analysis of clinical data of 22 patients, who were exposed to sunitinib for at least 1 year, was conducted to evaluate the long-term efficacy and safety of sunitinib for the treatment of mRCC.

METHODSA total of 54 patients with mRCC were treated with sunitinib malate, 50 mg/d orally, on a 4-weeks-on and 2-weeks-off dosing schedule in Peking University First Hospital. Treatment continued until disease progression, unacceptable adverse events (AEs), or death. Among them, 22 patients continued treatment for at least 1 year. The clinical data of these 22 patients were prospectively collected for analysis. AEs were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0. Tumor response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors.

RESULTSMedian progression-free survival was 19.5 months until last follow-up. The best efficacy results achieved were complete response, partial response, and stable disease for 2, 9, and 11 patients, respectively. Objective response rate was 50%. The most common AEs were hand-foot syndrome (95%) and hypertension (91%). Other common AEs were thyroid-stimulating hormone elevation (82%), platelet decrease (77%), and loss of appetite (77%). Only one patient withdrew from treatment for cardiac infarction. Another nine patients experienced dose modifications or short-term suspensions.

CONCLUSIONLong-term exposure to sunitinib malate showed encouraging efficacy in the treatment of mRCC. At the same time, the tolerability was good.

Adult ; Aged ; Antineoplastic Agents ; administration & dosage ; Carcinoma, Renal Cell ; drug therapy ; pathology ; Drug Administration Schedule ; Female ; Follow-Up Studies ; Humans ; Indoles ; administration & dosage ; Kidney Neoplasms ; drug therapy ; pathology ; Male ; Middle Aged ; Neoplasm Metastasis ; Pyrroles ; administration & dosage ; Young Adult

The purpose of this study was to investigate the effects of fluvastatin on the pharmacokinetics of repaglinide in rats. The effect of fluvastatin on P-glycoprotein and CYP3A4 activity was evaluated. The pharmacokinetic parameters and blood glucose concentrations were also determined after oral and intravenous administration of repaglinide to rats in the presence and absence of fluvastatin. Fluvastatin inhibited CYP3A4 activity in a concentration-dependent manner with a 50% inhibition concentration(IC50) of 4.1 microM and P-gp activity. Compared to the oral control group, fluvastatin significantly increased the AUC and the peak plasma level of repaglinide by 45.9% and 22.7%, respectively. Fluvastatin significantly decreased the total body clearance (TBC) of repaglinide compared to the control. Fluvastatin also significantly increased the absolute bioavailability (BA) of repaglinide by 46.1% compared to the control group. Moreover, the relative BA of repaglinide was 1.14- to 1.46-fold greater than that of the control. Compared to the i.v. control, fluvastatin significantly increased the AUC0-infinity of i.v. administered repaglinide. The blood glucose concentrations showed significant differences compared to the oral controls. Fluvastatin enhanced the oral BA of repaglinide, which may be mainly attributable to the inhibition of the CYP3A4-mediated metabolism of repaglinide in the small intestine and/or liver, to the inhibition of the P-gp efflux transporter in the small intestine and/or to the reduction of TBC of repaglinide by fluvastatin. The study has raised the awareness of potential interactions during concomitant use of repaglinide with fluvastatin. Therefore, the concurrent use of repaglinide and fluvastatin may require close monitoring for potential drug interactions.
Administration, Intravenous ; Animals ; Area Under Curve ; Biological Availability ; Blood Glucose ; Carbamates ; Drug Interactions ; Fatty Acids, Monounsaturated ; Indoles ; Intestine, Small ; Liver ; P-Glycoprotein ; Piperidines ; Plasma ; Rats