Suppressive Effect and Molecular Mechanism of Houttuynia cordata Thunb. Extract against Prostate Carcinogenesis and Castration-Resistant Prostate Cancer.

Houttuynia cordata Thunb. (HCT) is a well-known Asian medicinal plant with biological activities used in the treatment of many diseases including cancer. This study investigated the effects of HCT extract and its ethyl acetate fraction (EA) on prostate carcinogenesis and castration-resistant prostate cancer (CRPC). HCT and EA induced apoptosis in androgen-sensitive prostate cancer cells (LNCaP) and CRPC cells (PCai1) through activation of caspases, down-regulation of androgen receptor, and inactivation of AKT/ERK/MAPK signaling. Rutin was found to be a major component in HCT (44.00 ± 5.61 mg/g) and EA (81.34 ± 5.21 mg/g) in a previous study. Rutin had similar effects to HCT/EA on LNCaP cells and was considered to be one of the active compounds. Moreover, HCT/EA inhibited cell migration and epithelial-mesenchymal transition phenotypes via STAT3/Snail/Twist pathways in LNCaP cells. The consumption of 1% HCT-mixed diet significantly decreased the incidence of adenocarcinoma in the lateral prostate lobe of the Transgenic rat for adenocarcinoma of prostate model. Similarly, tumor growth of PCai1 xenografts was significantly suppressed by 1% HCT treatment. HCT also induced caspase-dependent apoptosis via AKT inactivation in both in vivo models. Together, the results of in vitro and in vivo studies indicate that HCT has inhibitory effects against prostate carcinogenesis and CRPC. This plant therefore should receive more attention as a source for the future development of non-toxic chemopreventive agents against various cancers.

Low Geriatric Nutritional Risk Index as a Poor Prognostic Marker for Second-Line Pembrolizumab Treatment in Patients with Metastatic Urothelial Carcinoma: A Retrospective Multicenter Analysis.

BACKGROUND: We evaluated the prognostic efficacy of the Geriatric Nutritional Risk Index (GNRI) in second-line pembrolizumab (PEM) therapy for patients with metastatic urothelial carcinoma (mUC). PATIENTS AND METHODS: From January 2018 to October 2019, 52 mUC patients, treated previously with platinum-based chemotherapy, underwent second-line PEM therapy. Peripheral blood parameters were measured at the start of treatment: serum neutrophil-to-lymphocyte ratio (NLR), serum albumin, serum C-reactive protein (CRP), and body height and weight. PEM was intravenously administered (200 mg every 3 weeks). The patients were organized into two groups based on their GNRI (<92 [low GNRI] and ≥92 [high GNRI]), and the data were retrospectively analyzed. Adverse events (AEs) were evaluated and imaging studies assessed for all patients. Analyses of survival and recurrence were performed using Kaplan-Meier curves. Potential prognostic factors affecting cancer-specific survival (CSS) were assessed by univariate and multivariate Cox regression analyses. RESULTS: patients' baseline characteristics, except for their BMI and objective response rate, did not significantly differ between the two groups. The median total number of cycles of PEM therapy was significantly higher for the high-GNRI group (n [range]: 6 [2-20] vs. 3 [1-6]). The median CSS with second-line PEM therapy was 3.6 months (95% confidence interval [CI]: 2.5-6.1) and 11.8 months (95% CI: 6.2-NA) in the low-GNRI and the high-GNRI group (p < 0.01), respectively. Significant differences in CSS between the low- and high-CRP or -NRL groups were not found. Multivariate Cox proportional-hazards regression analysis revealed that a poor Eastern Cooperative Oncology Group performance status, visceral metastasis, and a low GNRI were significant prognostic factors for short CSS (95% CI: 1.62-6.10, HR: 3.14; 95% CI: 1.13-8.11, HR: 3.03; 95% CI: 1.32-8.02, HR: 3.25, respectively). Of the AEs, fatigue showed a significantly higher incidence in the low-GNRI group. CONCLUSIONS: For mUC patients receiving second-line PEM therapy, the GNRI is a useful predictive biomarker for survival outcome.

Selective lysine-specific demethylase 1 inhibitor, NCL1, could cause testicular toxicity via the regulation of apoptosis.

BACKGROUND: Recent studies have shown that epigenetic alterations, such as those involving lysine-specific demethylase 1 (LSD1), lead to oncogenic activation and highlight such alterations as therapeutic targets. However, studies evaluating the effect of LSD1 inhibitors on male fertility are lacking. OBJECTIVES: We analyzed the potential toxicity of a new selective LSD1 inhibitor, N-[(1S)-3-[3-(trans-2-aminocyclopropyl)phenoxy]-1-(benzylcarbamoyl)propyl] benzamide (NCL1), in testes. MATERIALS AND METHODS: Human testicular samples were immunohistochemically analyzed. Six-week-old male C57BL/6J mice were injected intraperitoneally with dimethyl sulfoxide vehicle (n = 15), or 1.0 (n = 15) or 3.0 (n = 15) mg/kg NCL1 biweekly. After five weeks, toxicity and gene expression were analyzed in testicular samples by ingenuity pathway analysis (IPA) using RNA sequence data and quantitative reverse transcriptase (qRT)-PCR; hormonal damage was analyzed in blood samples. NCL1 treated GC-1, TM3, and TM4 cell lines were analyzed by cell viability, chromatin immunoprecipitation, flow cytometry, and Western blot assays. RESULTS: LSD1 was mainly expressed in human Sertoli and germ cells, with LSD1 levels significantly decreased in a progressive meiosis-dependent manner; germ cells showed similar expression patterns in normal spermatogenesis and early/late maturation arrest. Histological examination revealed significantly increased levels of abnormal seminiferous tubules in 3.0 mg/kg NCL1-treated mice compared to control, with increased cellular detachment, sloughing, vacuolization, eosinophilic changes, and TUNEL-positive cells. IPA and qRT-PCR revealed NCL1 treatment down-regulated LSD1 activity. NCL1 also reduced total serum testosterone levels. Western blots of mouse testicular samples revealed NCL1 induced a marked elevation in cleaved caspases 3, 7, and 8, and connexin 43 proteins. NCL1 treatment significantly reduced GC-1, but not TM3 and TM4, cell viability in a dose-dependent manner. In flow cytometry analysis, NCL1 induced apoptosis in GC-1 cells. CONCLUSIONS: High-dose NCL1 treatment targeting LSD1 caused dysfunctional spermatogenesis and induced caspase-dependent apoptosis. This suggests the LSD1 inhibitor may cause testicular toxicity via the regulation of apoptosis.

Hexane Insoluble Fraction from Purple Rice Extract Retards Carcinogenesis and Castration-Resistant Cancer Growth of Prostate Through Suppression of Androgen Receptor Mediated Cell Proliferation and Metabolism.

Prostate cancer and castration-resistant prostate cancer (CRPC) remain major health challenges in men. In this study, the inhibitory effects of a hexane insoluble fraction from a purple rice ethanolic extract (PRE-HIF) on prostate carcinogenesis and CRPC were investigated both in vivo and in vitro. In the Transgenic Rat for Adenocarcinoma of Prostate (TRAP) model, 1% PRE-HIF mixed diet-fed rats showed a significantly higher percentage of low-grade prostatic intraepithelial neoplasia and obvious reduction in the incidence of adenocarcinoma in the lateral lobes of the prostate. Additionally, 1% PRE-HIF supplied diet significantly suppressed the tumor growth in a rat CRPC xenograft model of PCai1 cells. In LNCaP and PCai1 cells, PRE-HIF treatment suppressed cell proliferation and induced G0/G1 cell-cycle arrest. Furthermore, androgen receptor (AR), cyclin D1, cdk4, and fatty acid synthase expression were down-regulated while attenuation of p38 mitogen-activated protein kinase, and AMP-activated protein kinase α activation occurred in PRE-HIF treated prostate cancer cells, rat prostate tissues, and CRPC tumors. Due to consistent results with PRE-HIF in PCai1 cells, cyanidin-3-glucoside was characterized as the active compound. Altogether, we surmise that PRE-HIF blocks the development of prostate cancer and CRPC through the inhibition of cell proliferation and metabolic pathways.

Antimicrobial susceptibility of pathogens in acute uncomplicated cystitis cases in the urology department of a community hospital in Japan: Comparison with treatment outcome and hospital-wide antibiogram.

We hypothesized that cases of uncomplicated cystitis treated in a Urology Department would display higher antimicrobial susceptibility than those reported by the hospital antibiogram. This would suggest narrow spectrum antibiotics could still be an effective treatment for uncomplicated cystitis despite this era of antimicrobial resistance. The objective of this study was thus to evaluate the rates of antimicrobial susceptibility of isolates cultured from uncomplicated cystitis cases that presented to the Urology Department of a community hospital in Japan. We evaluated the efficacy of cefaclor, a narrow spectrum antibiotic, for uncomplicated cystitis. We further compared the rates of antimicrobial susceptibility of isolates from uncomplicated cystitis cases to those reported in a hospital-wide antibiogram. A retrospective chart review was performed of patients diagnosed with uncomplicated cystitis in the Urology Department. The patients were mainly treated orally by cefaclor at 750 mg/day for seven days. Significantly greater susceptibilities to cefazolin (87.0% vs 65.7%), trimethoprim-sulfamethoxazole (89.4% vs 79.1%) and levofloxacin (84.6% vs 66.9%) were observed in a cystitis antibiogram for Escherichia coli compared with a hospital-wide antibiogram. The clinical efficacy of cefaclor for acute cystitis was also demonstrated. The greater susceptibility of Escherichia coli to antimicrobials observed in this study supports the hypothesis that antimicrobial susceptibility rates in uncomplicated cystitis cases that present to the Urology Department would be greater than those reported in the hospital antibiogram. Therefore, uncomplicated acute cystitis can be treated by narrow spectrum antibiotics such as cefaclor even in this ''antimicrobial resistance era''.

Transcatheter Arterial Embolization for Renal Angiomyolipoma Using a Micro-balloon Catheter and a Mixture of Ethanol and Lipiodol.

PURPOSE: To evaluate the efficacy and safety of transcatheter arterial embolization (TAE) for renal angiomyolipoma (AML) using a micro-balloon catheter and a mixture of ethanol and lipiodol. MATERIALS AND METHODS: Twelve consecutive patients with 15 AMLs, 9 females and 3 males, with a median age of 44 years (range, 11-81), underwent this procedure between 2011 and 2016. In all procedures, a micro-balloon catheter was advanced to the feeding artery of the AML and TAE was performed with a mixture of ethanol and lipiodol under balloon inflation. We reviewed medical records and images, and evaluated the technical success rate, clinical success rate, and complications. Technical success was defined as completion of TAE using the micro-balloon catheter and the mixture of ethanol and lipiodol. Clinical success was defined as reduction of tumor size on CT, which was performed before and after TAE. RESULTS: In 14 of 15 AMLs, the micro-balloon catheter could be advanced to the feeding artery, and TAE was performed successfully. Thus, the technical success rate was 93%. Among these 14 AMLs of 11 patients, 13 AMLs of 10 patients could be followed and tumor shrinkage was confirmed in all. Thus, the clinical success rate was 100%. Four patients had mild symptoms after TAE; the minor complication rate was 33% (4/12), and the major complication rate was 0%. CONCLUSION: TAE for renal AML using the micro-balloon catheter and mixture of ethanol and lipiodol appears to be effective and safe.

Curcumin-loaded PLGA nanoparticles conjugated with anti- P-glycoprotein antibody to overcome multidrug resistance.

BACKGROUND: The encapsulation of curcumin (Cur) in polylactic-co-glycolic acid (PLGA) nanoparticles (Cur- NPs) was designed to improve its solubility and stability. Conjugation of the Cur-NPs with anti-P-glycoprotein (P-gp) antibody (Cur-NPs-APgp) may increase their targeting to P-gp, which is highly expressed in multidrug- resistance (MDR) cancer cells. This study determined whether Cur-NPs-APgp could overcome MDR in a human cervical cancer model (KB-V1 cells) in vitro and in vivo. MATERIALS AND METHODS: First, we determined the MDR- reversing property of Cur in P-gp-overexpressing KB-V1 cells in vitro and in vivo. Cur-NPs and Cur-NPs-APgp, in the range 150-180 nm, were constructed and subjected to an in vivo pharmacokinetic study compared with Cur. The in vitro and in vivo MDR-reversing properties of Cur-NPs and Cur-NPs-APgp were then investigated. Moreover, the stability of the NPs was determined in various solutions. RESULTS: The combined treatment of paclitaxel (PTX) with Cur dramatically decreased cell viability and tumor growth compared to PTX treatment alone. After intravenous injection, Cur-NPs-APgp and Cur-NPs could be detected in the serum up to 60 and 120 min later, respectively, whereas Cur was not detected after 30 min. Pretreatment with Cur-NPs-APgp, but not with NPs or Cur-NPs, could enhance PTX sensitivity both in vitro and in vivo. The constructed NPs remained a consistent size, proving their stability in various solutions. CONCLUSIONS: Our functional Cur-NPs-APgp may be a suitable candidate for application in a drug delivery system for overcoming drug resistance. The further development of Cur-NPs-APgp may be beneficial to cancer patients by leading to its use as either as a MDR modulator or as an anticancer drug.

Thermotherapy using magnetic cationic liposomes powerfully suppresses prostate cancer bone metastasis in a novel rat model.

BACKGROUND: Bone metastasis is a serious problem for individuals with prostate cancer, and the effects of the anticancer drug docetaxel (DTX) are insufficient. We therefore examined the therapeutic potential of magnetic cationic liposomes (MCL) in a novel rat model that allows the evaluation of tumor immunity. The effects of MCL thermotherapy were compared with those of DTX as a conventional therapy for the treatment of bone metastatic prostate cancer. METHODS: Prostate tumor tissues were transplanted into the femurs of model rats divided into four groups: control, MCL, DTX, and MCL + DTX. Tumors were injected with MCL, and alternating magnetic field (AMF) irradiation was performed three times a week. Tumor proliferation and bone destruction were evaluated by proliferating cell nuclear antigen positivity, computed tomography, and CD68-positive cell number, while tumor immunity was evaluated by heat shock protein (HSP) 70 expression and CD8-positive lymphocyte number. RESULTS: We successfully established a novel femur metastasis model of prostate cancer, and demonstrated that tumor proliferation and bone destruction in the MCL and MCL + DTX groups were significantly suppressed compared with control and DTX groups. MCL thermotherapy concurrently induced necrosis and apoptosis. The expression of HSP70 in the MCL and MCL + DTX groups was also significantly increased, and tumor immunity was enhanced through the induction of CD8-positive lymphocytes. CONCLUSION: MCL thermotherapy was clearly more effective than DTX in treating bone metastatic prostate cancer. A combination of MCL thermotherapy and DTX therefore deserves consideration as a novel treatment for this disease.

Effect of heat therapy using magnetic nanoparticles conjugated with cationic liposomes on prostate tumor in bone.

BACKGROUND: We have developed magnetite nanoparticles conjugated with cationic liposomes (MCLs) to induce intracellular hyperthermia with exposure to an alternating magnetic field (AMF). We have previously demonstrated the hyperthermic effect of MCLs against certain types of malignant tumor cells in vivo. Here, we examine the effects of MCL + AMF heat therapy on prostate cancer tissue in a bone microenvironment and on bone destruction in a rat model. MATERIALS AND METHODS: Rat prostate cancer nodules were transplanted onto the calvaria of 6-week-old F344 male rats. MCLs were injected into the tumor which reached 7 mm in diameter, and then the animals were exposed to repeated AMF irradiation. The distribution of MCL, tumor necrosis, cell proliferation, and bone destruction in the bone microenvironment were evaluated. RESULTS: MCL + AMF heat therapy suppressed tumor growth on the calvaria, and histologically, the induction of a necrotic mass was observed around magnetic particles in the tumor. The bone destruction index, which indicates the degree of osteolysis associated with prostate tumor growth in the bone microenvironment, was 34.8% in the MCL group and 67.2% in the control group with significant difference. However, almost half of rats were dead in this experiment. CONCLUSION: MCL + AMF heat therapy suppressed tumor proliferation in the bone microenvironment, in addition to bone destruction. However, this method may exhibit side effects for central nerve system. If MCL are specifically taken into the prostate cancer cells in the bone microenvironment, this method may be useful for the treatment of bone metastatic lesions of prostate cancer.