Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 60
Filter
1.
Toxicol Appl Pharmacol ; 479: 116728, 2023 11 15.
Article in English | MEDLINE | ID: mdl-37858873

ABSTRACT

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men. To elucidate the connection between trace elements (arsenic: As, cadmium: Cd, lead: Pb, chromium: Cr, and nickel: Ni) and the risk of PCa, we analyzed trace element levels in the serum, urine, and tissues of PCa patients, while also examining their smoking status. We correlated these levels with their smoking habits. Notably, levels of Cd (P ≤ 0.05) and As (P ≤ 0.01) were significantly higher in the tumor tissue than in adjacent tissues. No significant differences were observed in the levels of Pb, Cr and Ni. Additionally, urinary Cd levels in 70% and arsenic levels in 2.3% of the PCa cohort were markedly higher than the CDC-reported cutoff (Cd ≤ 0.185 µg/L & As ≤100 µg/L). None displayed elevated levels of urinary Pb, Cr, and Ni. Conversely, in serum samples, the concentration of arsenic exceeded the CDC-determined limit (As ≤1.0 µg/L) in 31.69% of PCa patients. However, only 7.04% of patients had higher serum Cd levels than the CDC standard values (Cd ≤ 0.315 µg/L), while all PCa patients exceeded the Cr CDC limit (Cr ≤ 0.16 µg/L) and the Ni CDC limit (Ni ≤ 0.2 µg/L). On the contrary, no significant differences were observed in serum Pb (Pb ≤ 35.0 µg/L). Our findings establish a positive link between Cd and arsenic tissue concentrations and the risk of PCa. Subsequent studies are essential to determine whether elevated trace element levels pose a risk for the development of prostate carcinogenesis. Interestingly, among the PCa cohort comprising smokers, notably higher Cd levels were observed only in tumor tissues (P ≤ 0.01) and urine (P ≤ 0.05) compared to other elements or in other specimens.


Subject(s)
Arsenic , Metals, Heavy , Prostatic Neoplasms , Trace Elements , Male , Humans , Trace Elements/urine , Cadmium/urine , Arsenic/urine , Lead , Environmental Monitoring , Prostatic Neoplasms/epidemiology , Metals, Heavy/analysis
2.
World J Urol ; 41(9): 2413-2420, 2023 Sep.
Article in English | MEDLINE | ID: mdl-37530808

ABSTRACT

OBJECTIVE: This research endeavored to determine the key demographic and pathological factors tied to secondary malignant neoplasms (SMNs) in survivors of testicular cancer and to develop a predictive model. METHOD: A total of 53,309 testicular cancer patients from the SEER national database (1975-2016) were included in our analysis. The primary outcome measured was SMNs-free survival, defined as the duration from testicular cancer diagnosis to the detection of a non-testicular malignancy. The secondary outcome was SMN-specific survival, defined as the period from testicular cancer diagnosis until the patient's death due to SMNs. FINDINGS: Of the patients in the SEER cohort, 2978 (5.6%) developed non-testicular cancer SMNs. Higher age, receipt of chemotherapy, and radiation treatment were all significantly associated with the development of SMNs in survivors of testicular cancer (all p < 0.001). Kaplan-Meier analysis revealed a worse SMNs-free survival and poor SMN-specific survival in patients who underwent radiation therapy (both p < 0.001). Multivariable Cox regression analysis found non-Hispanic Black ethnicity, higher age, chemotherapy, and radiation therapy to be significantly associated with worse SMNs-free survival (p = 0.002, p < 0.001, p < 0.001, and p < 0.001, respectively), while lymphoma histology was associated with better SMNs-free survival (p < 0.001). The most common SMN types in patients receiving radiation therapy were prostate, lung, and bladder cancers. Predictive nomograms for SMNs-free survival and SMNs-specific survival were developed, with a C-index of 0.776 and 0.824, respectively. CONCLUSION: The age of diagnosis, non-Hispanic Black ethnicity, lymphoma histology, and treatment history with chemotherapy and radiation therapy were identified as prognostic factors for SMNs-free survival.


Subject(s)
Cancer Survivors , Neoplasms, Second Primary , Neoplasms , Male , Humans , Incidence , Neoplasms, Second Primary/epidemiology , Risk Factors , Survivors , Neoplasms/complications
3.
Front Pharmacol ; 14: 1137783, 2023.
Article in English | MEDLINE | ID: mdl-36937838

ABSTRACT

We investigated the efficacy of a small molecule ASR-600, an analog of Urolithin A (Uro A), on blocking androgen receptor (AR) and its splice variant AR-variant 7 (AR-V7) signaling in castration-resistant prostate cancer (CRPC). ASR-600 effectively suppressed the growth of AR+ CRPC cells by inhibiting AR and AR-V7 expressions; no effect was seen in AR- CRPC and normal prostate epithelial cells. Biomolecular interaction assays revealed ASR-600 binds to the N-terminal domain of AR, which was further confirmed by immunoblot and subcellular localization studies. Molecular studies suggested that ASR-600 promotes the ubiquitination of AR and AR-V7 resulting in the inhibition of AR signaling. Microsomal and plasma stability studies suggest that ASR-600 is stable, and its oral administration inhibits tumor growth in CRPC xenografted castrated and non-castrated mice. In conclusion, our data suggest that ASR-600 enhances AR ubiquitination in both AR+ and AR-V7 CRPC cells and inhibits their growth in vitro and in vivo models.

4.
Free Radic Biol Med ; 199: 44-55, 2023 04.
Article in English | MEDLINE | ID: mdl-36764624

ABSTRACT

Chronic exposure to cadmium (Cd), a class I carcinogen, leads to malignant transformation of normal prostate epithelial cells (RWPE-1). The constant generation of Cd-induced ROS and resulting ER stress induces cellular responses that are needed for cell survival, and autophagy has an important role in this process. However, the mechanisms that regulate Cd-induced ROS and how these differ in terms of acute and chronic cadmium exposure remain unexplained. Here, we show that acute or chronic Cd exposure facilitates NOX1 assembly by activating its cytosolic regulators p47phox and p67phox in RWPE-1 cells. Upregulation of NOX1 complex proteins and generation of ROS activates unfolded protein response (UPR) via phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor 2 alpha (eIF2α), and selective translation of activating transcription factor 4 (ATF4). Chronic Cd exposure constantly activates NOX1 complex and generates consistent ROS and ER stress that led to defective autophagy, wherein ATG5 expression is downregulated in contrast to acute Cd exposure. As a result, selective/defective autophagy creates depletion of autophagosome-lysosome fusion that gives a survival advantage to transforming cells, which is not available to RWPE-1 cells acutely exposed to Cd. Knockdown of key molecules in a lockstep manner directly affects the most downstream autophagy pathways in transforming cells. Overall, this study demonstrates that assembly of NOX1 complex proteins is indispensable for Cd-induced persistent ROS and controls ER stress-induced defective autophagy in mice and humans.


Subject(s)
Cadmium , Prostate , Humans , Male , Animals , Mice , Prostate/metabolism , Cadmium/toxicity , Reactive Oxygen Species/metabolism , Autophagy/genetics , Endoplasmic Reticulum Stress/genetics , Cell Transformation, Neoplastic/metabolism , Apoptosis , Activating Transcription Factor 4/metabolism , NADPH Oxidase 1/genetics , NADPH Oxidase 1/metabolism
5.
Cureus ; 15(12): e50173, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38186507

ABSTRACT

Urology has shown a gradual decrease in the number of graduating residents who plan to pursue a career in academic medicine. Our objective was to identify barriers to academic urology, present options to mitigate those barriers, and explore strategic ways to encourage trainees to seek careers in academic urology. The authors performed a contemporary review of relevant articles through PubMed assessing prior survey studies, editorials, and expert opinion articles that evaluated academic urology, perceptions of academic medicine, physician burnout, and barriers that have been identified to pursuing careers in academic medicine. Selected articles were then independently reviewed by three authors for relevance and application of factors mitigating perceived barriers to pursuing a career in academic medicine, specifically academic urology. Barriers at the academic levels of medical school and residency were found to consist of the following: lack of exposure to research early in their medical careers, inadequate mentorship, all-specialty leading levels of burnout, current average levels of medical school indebtedness contrasted to perceptions of pay disparity when compared to private practice urologists' income, and perceptions of difficulty in maintaining the academic "triple threat." More acutely, the decision to make Step 1 a pass/fail exam, with the addition of historically low match rates in urology, have resulted in additional complications and concerns for aspiring academic urologists. There are clear barriers that graduating urology residents encounter when considering a career in academic medicine. In this review, we present possible mitigating factors that may be instituted at the individual, medical school, and postgraduate levels to increase the number of practicing academics.

6.
Urol Oncol ; 39(12): 835.e9-835.e17, 2021 12.
Article in English | MEDLINE | ID: mdl-34049782

ABSTRACT

INTRODUCTION AND OBJECTIVES: To evaluate the prognostic role of albumin-to-fibrinogen ratio (AFR) for the prediction of oncological outcomes in a multi-institutional cohort of bladder cancer (BC) patients treated with radical cystectomy (RC). MATERIALS AND METHODS: We retrospectively analyzed a multicenter cohort of patients treated with upfront RC for localized (cT1-4aN0M0) BC. Multivariable logistic regression analyses were performed to evaluate the ability of AFR to predict non-organ confined (NOC) disease and lymph-node involvement (LNI) at time of RC. Multivariable Cox' regression models were performed to evaluate the prognostic effect of AFR on Time-to-Progression (TTP), overall survival (OS), and cancer-specific survival (CSS). RESULTS: A cut-off value to discriminate between low and high AFR was determined by calculating the receiver operating characteristic (ROC) curve. The area under the curve was 0.73 with an optimal cut-off at 9.53. Data were available for 246 patients (91 with low AFR, 155 with high AFR). Low AFR was associated with characteristics of tumor aggressiveness and independently predicted NOC (OR 2.11, P = 0.02) and LNI (OR 1.58, P = 0.04) at final pathological report. On multivariable Cox' regression analyses, preoperative low AFR was independently associated with worse TTP (HR 2.21, P = 0.02), OS (HR 2.24, P = 0.03), and CSS (HR 2.70, P = 0.01). CONCLUSION: Preoperative low AFR is a prognostic biomarker for worse TTP, OS, CSS, and is independently associated with adverse tumor pathological features in BC patients undergoing RC. Our results suggest that especially patients with low AFR may be considered for neoadjuvant treatment.


Subject(s)
Albumins/metabolism , Cystectomy/methods , Fibrinogen/metabolism , Urinary Bladder Neoplasms/blood , Urinary Bladder Neoplasms/surgery , Aged , Female , Humans , Male , Prognosis , Retrospective Studies
7.
Semin Cancer Biol ; 76: 247-257, 2021 11.
Article in English | MEDLINE | ID: mdl-33798723

ABSTRACT

Environmental and/or occupational exposure to metals such as Arsenic (As), Cadmium (Cd), and Chromium (Cr) have been shown to induce carcinogenesis in various organs, including the urogenital system. However, the mechanisms responsible for metal-induced carcinogenesis remain elusive. We and others have shown that metals are potent inducers of autophagy, which has been suggested to be an adaptive stress response to allow metal-exposed cells to survive in hostile environments. Albeit few, recent experimental studies have shown that As and Cd promote tumorigenesis via autophagy and that inhibition of autophagic signaling suppressed metal-induced carcinogenesis. In light of the newly emerging role of autophagic involvement in metal-induced carcinogenesis, the present review focuses explicitly on the mechanistic role of autophagy and potential signaling pathways involved in As-, Cd-, and Cr-induced urogenital carcinogenesis.


Subject(s)
Autophagy/physiology , Carcinogenesis/chemically induced , Metals/adverse effects , Urogenital Neoplasms/chemically induced , Urogenital Neoplasms/pathology , Animals , Arsenic/adverse effects , Cadmium/adverse effects , Chromium/adverse effects , Environmental Exposure/adverse effects , Humans , Occupational Exposure/adverse effects
8.
Transl Res ; 231: 92-101, 2021 05.
Article in English | MEDLINE | ID: mdl-33279680

ABSTRACT

Currently, clinicians rely on clinical nomograms to stratify progression risk at the time of diagnosis in patients with prostate cancer (CaP). However, these tools may not accurately distinguish aggressive potential in low-grade CaP. The current study determined the diagnostic potential of 3 molecular markers (ROCK1, RUNX3, and miR-301a) in terms of their ability to identify which low-grade tumors are likely to progress. Real-time PCR and immunohistochemical analysis were used to assess ROCK1, RUNX3, and miR-301a expression profiles in 118 serum and needle biopsy specimens. Expressions of ROCK1 and miR-301a were found to be significantly higher in Gleason 6 and 7 CaP as compared to BPH, while an inverse trend was observed with RUNX3. Further, incorporation of all 3 molecular markers significantly improved clinical nomograms' diagnostic accuracy and correlated with disease progression. Hence, in conclusion, the inclusion of these 3 molecular markers identified aggressive phenotype and predicted disease progression in low-grade CaP tumors at the time of diagnosis.


Subject(s)
Biomarkers, Tumor/blood , Core Binding Factor Alpha 3 Subunit/metabolism , MicroRNAs/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , rho-Associated Kinases/metabolism , Aged , Aged, 80 and over , Biomarkers, Tumor/metabolism , Biopsy , Core Binding Factor Alpha 3 Subunit/genetics , Gene Expression Regulation, Neoplastic , Humans , Male , MicroRNAs/genetics , Middle Aged , Polymerase Chain Reaction , rho-Associated Kinases/genetics
9.
Mol Cancer Ther ; 19(12): 2422-2431, 2020 12.
Article in English | MEDLINE | ID: mdl-33087513

ABSTRACT

Notch1 activation triggers significant oncogenic signaling that manifests as enhanced metastatic potential and tumorigenesis in colorectal cancer. Novel small-molecule inhibitors, mainly plant-derived analogs, have low toxicity profiles and higher bioavailability. In this study, we have developed a small molecule, ASR490, by modifying structure of naturally occurring compound Withaferin A. ASR490 showed a growth-inhibitory potential by downregulating Notch1 signaling in HCT116 and SW620 cell lines. Docking studies and thermal shift assays confirmed that ASR490 binds to Notch1, whereas no changes in Notch2 and Notch3 expression were seen in colorectal cancer cells. Notch1 governs epithelial-to-mesenchymal transition signaling and is responsible for metastasis, which was abolished by ASR490 treatment. To further confirm the therapeutic potential of ASR490, we stably overexpressed Notch1 in HCT-116 cells and determined its inhibitory potential in transfected colorectal cancer (Notch1/HCT116) cells. ASR490 effectively prevented cell growth in both the vector (P = 0.005) and Notch1 (P = 0.05) transfectants. The downregulation of Notch1 signaling was evident, which corresponded with downregulation of mesenchymal markers, including N-cadherin and ß-catenin and induction of E-cadherin in HCT-116 transfectants. Intraperitoneal administration of a 1% MTD dose of ASR490 (5 mg/kg) effectively suppressed the tumor growth in control (pCMV/HCT116) and Notch1/HCT116 in xenotransplanted mice. In addition, downregulation of Notch1 and survival signaling in ASR-treated tumors confirmed the in vitro results. In conclusion, ASR490 appears to be a potent agent that can inhibit Notch1 signaling in colorectal cancer.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/genetics , Gene Expression Regulation, Neoplastic/drug effects , Receptor, Notch1/genetics , Biomarkers , Cell Line, Tumor , HCT116 Cells , Humans , Receptor, Notch1/metabolism , Receptor, Notch2/genetics , Receptor, Notch2/metabolism , Receptor, Notch3/genetics , Receptor, Notch3/metabolism
10.
J Sex Med ; 17(11): 2287-2290, 2020 11.
Article in English | MEDLINE | ID: mdl-32883632

ABSTRACT

BACKGROUND: Implantation of an inflatable penile prosthesis (IPP) has high success and satisfaction rates, but there remains a paucity of evidence examining non-usage of IPP and reasons for discontinuation. AIM: To identify how frequent patients use their prosthesis and their personal reasons for no longer using it. METHODS: We conducted a survey of all patients who underwent an IPP implantation by a single surgeon over a 6-year period, between 2012 and 2018. After application of inclusion and exclusion criteria, a total of 114 patients formed the final cohort. Patients were initially surveyed via mail with a questionnaire; those who did not respond were surveyed via telephone. The factors determining patient selection for IPP implantation included suitability for general anesthesia, manual dexterity to use the device by the patient or their partner on a demonstration device, and presence of refractory erectile dysfunction, HbA1C lower than 8.5, or need for a revision of a previously placed IPP. Universally, a 3-piece AMS 700 Series implant was placed via the penoscrotal approach. Data were analyzed with Pearson chi square test, and survivability of the device was assessed with Kaplan-Meier survival curve. OUTCOMES: The main outcomes of this study are the frequency of IPP usage and reasons for discontinuation. RESULTS: The survey participation rate was 97%. The mean age of patient was 64 years (range 34-83 years), and the mean time between surgery and completion of survey was 2.98 years (range 0.25-7.4 years). Kaplan-Meier curve demonstrated that 68% of the patients were using the IPP at 5 years after implantation. Using the age 70 years as a cutoff, 18 (22%) patients younger than 70 years and 14 (42%) patients older than 70 years discontinued using the IPP (P = .029). The commonest reasons for discontinuation were poor health to engage in sexual activity (2.6%), loss of companion (19%), loss of interest in sex (2.6%), and device malfunction with no further interest in revision of prosthesis (14%). CLINICAL IMPLICATIONS: The clinical implication of this study was improved patient selection for device implantation. STRENGTHS AND LIMITATIONS: To our knowledge, no other study has investigated reasons for patients no longer using their prosthesis. Our study has several limitations including that it is a cross-sectional analysis, our survey is not validated, this is a single-surgeon experience, we have a small sample size, and we did not differentiate between virgin implant and reimplantation. CONCLUSION: Our study shows a high rate (28%) of non-usage of IPP, more so in men older than the age of 70 years in the first 5 years of implantation. Knoll P, Rai S, Talluri S, et al. A Survey of Usage of Penile Prosthesis. J Sex Med 2020;17:2287-2290.


Subject(s)
Erectile Dysfunction , Penile Implantation , Penile Prosthesis , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Erectile Dysfunction/surgery , Humans , Male , Middle Aged , Patient Satisfaction , Prosthesis Design , Retrospective Studies , Surveys and Questionnaires
11.
Oncol Lett ; 20(1): 850-860, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32566012

ABSTRACT

Due to a lack of mechanistic insights, muscle-invasive bladder cancer (MIBC) remains incurable and is one of the most lethal types of cancer in the United States. The present study investigated changes in the molecular signatures of MIBC cells (TCCSUP and HT1376) after treatment with a novel small molecule, ASR488, to gain knowledge of the mechanisms that inhibited MIBC cell growth. ASR488 treatment initiated apoptotic signaling in MIBC cells. Pathway enrichment analysis was used to analyze the changes in function of differentially expressed genes. Gene Ontology analysis, as well as Kyoto Encyclopedia of Genes and Genomes analysis, was also performed. These analyses along with reactome pathway enrichment analyses indicated that the genes upregulated in the ASR488-treated cells are involved in focal adhesion, neurotrophin signaling, p53 signaling, endoplasmic reticulum functioning in terms of protein processing, and pathways related to bladder cancer. The genes downregulated in ASR488-treated MIBC cells were mainly involved in DNA replication, mismatch repair, RNA degradation, nucleotide excision repair and TGFß signaling (P<0.05). Furthermore, reverse transcription-quantitative PCR analysis revealed an increase in transcripts of the most upregulated genes in ASR 488-treated MIBC cells: CPEB1 (36-fold), IL11 (30-fold), SFN (20.12-fold) and CYP4F11 (15.8-fold). In conclusion, the analysis of biological functions of the most differentially expressed genes revealed possible mechanisms that may be associated with the aggressiveness of MIBC.

12.
Int Urogynecol J ; 31(9): 1969-1971, 2020 09.
Article in English | MEDLINE | ID: mdl-32227264

ABSTRACT

INTRODUCTION AND HYPOTHESIS: Iatrogenic ureteral injuries can occur during any surgery but are more likely to occur during urologic and gynecologic procedures. The middle and distal ureter are especially at risk of injury during these surgeries. METHODS: The objective of this surgical educational video was to demonstrate how to repair middle to distal ureteral injuries with the following techniques: direct ureteroureterostomy, ureteroneocystotomy, vesico-psoas hitch, and Boari-Ockerblad bladder flap. RESULTS: A female cadaver was used to show how to surgically repair injuries to the middle and distal ureter. CONCLUSIONS: Middle to distal ureteral injuries occurring during urologic and gynecologic surgeries can be repaired by the techniques demonstrated in this video manuscript.


Subject(s)
Ureter , Urologic Surgical Procedures , Cadaver , Female , Gynecologic Surgical Procedures/adverse effects , Humans , Ureter/surgery , Urinary Bladder , Urologic Surgical Procedures/adverse effects
13.
Oncogenesis ; 9(2): 23, 2020 Feb 17.
Article in English | MEDLINE | ID: mdl-32066655

ABSTRACT

Epidemiological evidence suggests that cadmium (Cd) is one of the causative factors of prostate cancer, but the effect of Cd on benign prostatic hyperplasia (BPH) remains unclear. This study aimed to determine whether Cd exposure could malignantly transform BPH1 cells and, if so, to dissect the mechanism of action. We deciphered the molecular signaling responsible for BPH1 transformation via RNA-sequencing and determined that Cd induced the expression of zinc finger of the cerebellum 2 (ZIC2) in BPH1 cells. We noted Cd exposure increased ZIC2 expression in the Cd-transformed BPH1 cells that in turn promoted anchorage-independent spheroids and increased expression of stem cell drivers, indicating their role in stem cell renewal. Subsequent silencing of ZIC2 expression in transformed cells inhibited spheroid formation, stem cell marker expression, and tumor growth in nude mice. At the molecular level, ZIC2 interacts with the glioma-associated oncogene family (GLI) zinc finger 1 (GLI1), which activates prosurvival factors (nuclear factor NFκB, B-cell lymphoma-2 (Bcl2), as well as an X-linked inhibitor of apoptosis protein (XIAP)) signaling in Cd-exposed BPH1 cells. Conversely, overexpression of ZIC2 in BPH1 cells caused spheroid formation confirming the oncogenic function of ZIC2. ZIC2 activation and GLI1 signaling induction by Cd exposure in primary BPH cells confirmed the clinical significance of this oncogenic function. Finally, human BPH specimens had increased ZIC2 versus adjacent healthy tissues. Thus, we report direct evidence that Cd exposure induces malignant transformation of BPH via activation of ZIC2 and GLI1 signaling.

14.
Urol Oncol ; 37(7): 492-502, 2019 07.
Article in English | MEDLINE | ID: mdl-31006613

ABSTRACT

PURPOSE: The role of androgen receptor (AR) signaling in bladder cancer (BCa) is not fully characterized. This study aimed to delineate the role of AR signaling in BCa and to determine whether the combination of AR inhibitor, Enzalutamide (Enz), and Cisplatin (Cis) efficiently inhibit the growth of BCa cells. METHODS: AR expression was determined in 89 human urothelial BCa specimens by immunohistochemistry. A panel of BCa cell lines was treated with Cis, Enz, or a combination of both (Enz + Cis). We determined the expression of AR, changes in apoptotic signaling, DNA damage, and analyzed effect on epithelial mesenchymal transformation markers. RESULT: AR expression was detected in 61.4% of tumors from male BCa patients. Inhibition of AR signaling by Enz effectively inhibited the growth of AR+ BCa cells by inducing apoptosis (26%) in AR+ TCCSUP (P = 0.0201) and J82 (15%, P = 0.0386) cells. Interestingly, Enz + Cis synergistically inhibited the proliferation of BCa cells even at low concentrations by inducing proapoptotic signaling in AR+ BCa cells. Invasive and migratory potential of TCCSUP and J82 cells were reduced with Enz + Cis treatment, and associated with down-regulation of mesenchymal markers. CONCLUSIONS: A high percentage of the bladder tumors from male patients in our cohort expressed AR. The combination of Enz and Cis synergistically inhibited growth of BCa cells more efficiently than single agent alone. This supports the rationale for future investigation of AR antagonists in combination with standard chemotherapy in MIBC.


Subject(s)
Androgen Receptor Antagonists/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Transitional Cell/drug therapy , Cisplatin/therapeutic use , Receptors, Androgen/metabolism , Urinary Bladder Neoplasms/drug therapy , Androgen Receptor Antagonists/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Benzamides , Carcinoma, Transitional Cell/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cisplatin/pharmacology , Cohort Studies , DNA Damage/drug effects , Drug Resistance, Neoplasm , Drug Synergism , Female , Humans , Male , Middle Aged , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/therapeutic use , Signal Transduction/drug effects , Treatment Outcome , Urinary Bladder/pathology , Urinary Bladder Neoplasms/pathology , Urothelium/pathology
15.
Toxicol Appl Pharmacol ; 373: 62-68, 2019 06 15.
Article in English | MEDLINE | ID: mdl-31002860

ABSTRACT

Earlier, we reported that chronic cadmium (Cd)-exposure to prostate epithelial (RWPE-1) cells causes defective autophagy, which leads to the transformation of a malignant phenotype in both in vitro and in vivo models. However, the upstream events responsible for defective autophagy are yet to be delineated. The present study suggests that chronic Cd exposure induces endoplasmic reticulum (ER) stress that triggers the phosphorylation of stress transducers [protein kinase R-like ER Kinase- (PERK), eukaryotic translation initiation factor 2-alpha- (eIF2-α) and Activating Transcription Factor 4 -(ATF-4)], resulting in defective autophagy that protects Cd-exposed RWPE-1 cells. On the other hand, inhibition of the ATF4 stress inducer by siRNA blocked the Cd-induced defective autophagy in transforming cells. While dissecting the upstream activators of ER stress, we found that increased expression of reactive oxygen species (ROS) is responsible for ER stress in Cd-exposed RWPE-1 cells. Overexpression of antioxidants (SOD1/SOD2) mitigates Cd-induced ROS that results in inhibition of ER stress and autophagy in prostate epithelial cells. These results suggest that the induction of ROS and subsequent ER stress are responsible for defective autophagy in Cd-induced transformation in prostate epithelial cells.


Subject(s)
Autophagy/drug effects , Cadmium/toxicity , Cell Transformation, Neoplastic/chemically induced , Endoplasmic Reticulum Stress/drug effects , Epithelial Cells/drug effects , Prostate/drug effects , Prostatic Neoplasms/chemically induced , Autophagy-Related Proteins/metabolism , Cell Line, Transformed , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Humans , Male , Oxidative Stress/drug effects , Phosphorylation , Prostate/metabolism , Prostate/pathology , Prostatic Neoplasms/genetics , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Reactive Oxygen Species/metabolism , Signal Transduction , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism
16.
Urol Oncol ; 36(11): 503.e9-503.e15, 2018 11.
Article in English | MEDLINE | ID: mdl-30195463

ABSTRACT

BACKGROUND: Prostate-specific antigen screening for prostate cancer (CaP) remains controversial. This study establishes the role of microRNA 301a (miR-301a) as a supplemental biomarker that can distinguish between patients with benign prostate hyperplasia and clinically significant CaP. We evaluate the ability of miR-301a to predict the adverse pathology of CaP. METHODS: In the first cohort, serum and prostate tumor samples were obtained from thirteen patients with Benign prostate hyperplasia (BPH), twelve patients with Gleason 6, and sixteen patients with Gleason 7 prostate adenocarcinoma. In the second cohort, 40 prostatectomy cases were selected (BPH:12, Gleason 6:12 and Gleason 7:16). MiRNA was extracted from serum and tumor samples. Quantitative reverse transcription-polymerase chain reaction was performed for detection of miR-301a. To understand the molecular role of miR-301a, we performed cell viability, Western blots, promoter analysis, overexpression, and silencing studies in BPH and DU-145 cell lines. RESULTS: MiR-301a demonstrated a significantly higher expression in both serum and tumor tissue in patients with CaP when compared to patients with BPH (P = 0.011 and 0.013 for serum and tissue expression, respectively). Expression of miR-301a in prostatectomy specimens correlated with increased Gleason score. We demonstrated that miR-301a inhibited the pro-apoptotic function of RUNX3, and activated ROCK1-mediated pro-survival signal in CaP. Silencing miR-301a initiated the pro-apoptotic function of RUNX3 by inhibiting ROCK1 expression in CaP cells. CONCLUSIONS: Expression of miR-301a could be a valuable adjunct tool for stratifying patients with elevated prostate-specific antigen, as well as those diagnosed with CaP. Including the miR-301a as an additional variable in MSKCC post-prostatectomy nomogram improved its ability in facilitating clinical decision-making.


Subject(s)
Adenocarcinoma/diagnosis , Biomarkers, Tumor/genetics , MicroRNAs/biosynthesis , Prostatic Neoplasms/diagnosis , Adenocarcinoma/mortality , Adult , Aged , Area Under Curve , Humans , Male , MicroRNAs/analysis , Middle Aged , Nomograms , Prognosis , Prostate-Specific Antigen/blood , Prostatic Neoplasms/mortality , ROC Curve
17.
Carcinogenesis ; 39(12): 1537-1547, 2018 12 31.
Article in English | MEDLINE | ID: mdl-30124785

ABSTRACT

Chemopreventive effects and associated mechanisms of withaferin A (WA) against intestinal and colon carcinogenesis remain unknown. We investigated the chemopreventive effect of WA on transgenic adenomatous polyposis coli (APCMin/+) mouse and chemically induced azoxymethane/dextran sodium sulfate (AOM/DSS) models of intestinal and colon carcinogenesis. Oral WA administration (4 and 3 mg/kg) inhibited tumor initiation and progression of intestinal polyps formation in APCMin/+ mice and colon carcinogenesis in the AOM/DSS mouse model. WA-administered mice showed a significant reduction in both number [duodenum, 33% (P > 0.05); jejunum, 32% (P < 0.025); ileum, 43% ( P < 0.001); and colon 59% (P < 0.01] and size of polyps in APCMin/+ mice compared with the respective controls. Similarly, tumor multiplicity was significantly reduced (P < 0.05) in the colon of WA-administered AOM/DSS mice. Pathological analysis showed reduced adenomas and tissue inflammation in WA-administered mouse models. Molecular studies suggested that WA inhibited the expression of inflammatory (interluekin-6, tumor necrosis factor-alpha and cyclooxygenase-2), pro-survival (pAKT, Notch1 and NF-κB) markers in APCMin/+ and AOM/DSS models. The results suggest that WA is a potent agent for preventing colon carcinogenesis and further investigation is required to show clinical utility of the agent.


Subject(s)
Anticarcinogenic Agents/pharmacology , Carcinogenesis/drug effects , Colon/drug effects , Colonic Neoplasms/prevention & control , Inflammation/drug therapy , Withanolides/pharmacology , Animals , Chemoprevention/methods , Colon/pathology , Colonic Neoplasms/pathology , Disease Models, Animal , Female , Inflammation/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic
18.
Mol Carcinog ; 57(10): 1332-1341, 2018 10.
Article in English | MEDLINE | ID: mdl-30069922

ABSTRACT

Androgen ablation therapy is the primary therapeutic option for locally advanced and metastatic castration-resistant prostate cancer (CRPC). We investigated therapeutic effect of a dietary metabolite Urolithin A (UroA) and dissected the molecular mechanism in CRPC cells. Treatment with UroA inhibited cell proliferation in both androgen receptor-positive (AR+ ) (C4-2B) and androgen receptor-negative (AR- ) (PC-3) cells however, AR+ CaP cells were more sensitive to UroA treatment as compared with AR- CaP cells. Inhibition of the AR signaling was responsible for the UroA effect on AR+ CaP cells. Ectopic expression of AR in PC-3 cells sensitized them to UroA treatment as compared to the vector-expresseing PC-3 cells, which suggests that AR could be a target of UroA. Similarly, in enzalutamide-resistant C4-2B cells, a downregulation of AR expression also suppressed cell proliferation which was observed with the UroA treatment. Oral administration of UroA significantly suppressed the growth of C4-2B xenografts (P = 0.05) compared with PC-3 xenografts (P = 0.069) without causing toxicity to animals. Immunohistochemistry analysis confirmed in vitro findings such as downregulation of AR/pAKT signaling in UroA-treated C4-2B tumors, which suggests that UroA may be a potent chemo-preventive and therapeutic agent for CRPC.


Subject(s)
Cell Proliferation/drug effects , Coumarins/pharmacology , Down-Regulation/drug effects , Prostatic Neoplasms, Castration-Resistant/drug therapy , Receptors, Androgen/metabolism , Xenograft Model Antitumor Assays , Animals , Apoptosis/drug effects , Apoptosis/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mice, Inbred BALB C , Mice, Nude , PC-3 Cells , Prostatic Neoplasms, Castration-Resistant/genetics , Prostatic Neoplasms, Castration-Resistant/metabolism , Receptors, Androgen/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Tumor Burden/drug effects , Tumor Burden/genetics
19.
Cell Death Dis ; 9(8): 798, 2018 07 23.
Article in English | MEDLINE | ID: mdl-30038258

ABSTRACT

Epithelial to mesenchymal transition (EMT) in colorectal cancer (CRC) has been attributed to activation of AKT and Notch1 signaling pathways. As EMT corresponds to increased aggressiveness of CRC, approaches that prevent metastasis by targeting AKT/Notch1 pathways are at the forefront of current research paradigms. This study examined the anti-metastatic potential of Verrucarin J (VJ), a small molecule, in CRC cells overexpressing AKT and Notch1. VJ significantly inhibited AKT/HCT 116 cell growth by acting on the AKT/NFκB/Bcl-2 signaling axis and initiated apoptotic signaling as was evident from increased expression of pro-apoptotic markers such as cleaved PARP, cleaved caspase 3, and cleaved caspase 9. Also, VJ inhibited the cell growth in AKT/Notch1-overexpressing CRC cells and abrogated EMT. The down-regulation of AKT and Notch1 signaling was apparent in immunoblot analysis and corresponded with down-regulation of mesenchymal markers including Snail, and ß-catenin. Intraperitoneal administration of VJ in control (pCMV/HCT 116) and AKT/HCT 116 mice significantly suppressed AKT-induced tumor growth in a xenograft model. In addition, down-regulation of prosurvival markers as well as AKT and Notch1 was observed in the immunohistochemical analysis of the xenografted tumors. In conclusion, our study substantiates the role of AKT and Notch1 in cell proliferation, angiogenesis, and EMT of CRC cells and demonstrates that VJ may be a viable therapeutic option to counter AKT-induced cell proliferation and tumor outgrowth in CRC.


Subject(s)
Down-Regulation/drug effects , Epithelial-Mesenchymal Transition/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Receptor, Notch1/metabolism , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement , Cell Proliferation , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Humans , Mice , Mice, Nude , Proto-Oncogene Proteins c-akt/genetics , Signal Transduction , Transplantation, Heterologous , Trichothecenes/pharmacology
20.
Genes Cancer ; 8(9-10): 713-724, 2017 Sep.
Article in English | MEDLINE | ID: mdl-29234489

ABSTRACT

Epidermal growth factor receptor (EGFR) activation events and the mammalian target of rampamycin (mTOR) are considered important therapeutic targets in alleviating cancer conditions. The current treatment paradigm has shifted to personalized treatment strategies with tyrosine kinase inhibitors (TKIs) or anaplastic lymphoma kinase (ALK) inhibitors, due to low survival rates in non-small cell lung cancer (NSCLC) in terms of the prevailing platinum-based therapy. In the present study, we examined the anticancer potential of Verrucarin J (VJ), a small molecule, in NSCLC cell lines (H460 and A549). The small molecule significantly inhibited cell growth, proliferation, colony forming ability, and induced apoptosis in both lung cancer cell lines. The inhibitory effects on EGFR (pEGFR -tyr1173) and AKT (pAKT Serine473) signaling, downregulates downstream pro-survival signaling (mTOR and NF-κB) in cancer cell lines. In addition, VJ abrogated invasive and migratory potential of A549 and H460 cells. We also observed a downregulation of mesenchymal markers such as N-cadherin, Slug, ß-catenin, and vimentin expression in both cell lines. Our results suggest that VJ inhibited cancer cell growth and could be a potent molecule to inhibit EGFR and AKT signaling in NSCLC.

SELECTION OF CITATIONS
SEARCH DETAIL
...