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Deng Z, Zhou F, Li M, Jin W, Yu J, Wang G, Qian K, Ju L, Zhang Y, Xiao Y, Wang X. DLGAP5 enhances bladder cancer chemoresistance by regulating glycolysis through MYC stabilization. Theranostics 2025; 15:2375-2392. [PMID: 39990228 PMCID: PMC11840727 DOI: 10.7150/thno.102730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 01/08/2025] [Indexed: 02/25/2025] Open
Abstract
Rationale: Bladder cancer (BLCA), one of the most lethal urological tumors, exhibits high rates of recurrence and chemoresistance, particularly to gemcitabine (GEM). Understanding the mechanisms of GEM resistance is crucial for improving therapeutic outcomes. Our study investigates the role of DLGAP5 in promoting GEM resistance through modulation of glycolysis and MYC protein stability in BLCA cells. Methods: We utilized various BLCA cell lines and clinical tissue samples to analyze the impact of DLGAP5 on GEM resistance. Through biochemical assays, protein interaction studies, and gene expression analyses, we examined how DLGAP5 interacts with USP11 and MYC, assessed the effects on MYC deubiquitination and stability. The influence of these interactions on glycolytic activity and GEM resistance was also evaluated via mouse subcutaneous xenograft model and spontaneous BLCA model. Results: Our findings indicate that DLGAP5 enhances GEM resistance by stabilizing MYC protein via deubiquitination, a process mediated by USP11. DLGAP5 was found to facilitate the interaction between USP11 and MYC, promoting MYC-driven transcription of DLGAP5 itself, thereby creating a positive feedback loop. This loop leads to sustained MYC accumulation and increased glycolytic activity, contributing to GEM resistance in BLCA cells. Conclusion: The study highlights the critical role of DLGAP5 in regulating MYC protein stability and suggests that disrupting the DLGAP5-USP11-MYC axis may provide a novel therapeutic approach to overcome GEM resistance in BLCA. DLGAP5 represents a potential target for therapeutic intervention aimed at mitigating chemoresistance in bladder cancer BLCA.
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Affiliation(s)
- Zhao Deng
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fenfang Zhou
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mingxing Li
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wan Jin
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China
- Euler Technology, ZGC Life Sciences Park, Beijing, China
| | - Jingtian Yu
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Gang Wang
- Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Kaiyu Qian
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Lingao Ju
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yi Zhang
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China
- Euler Technology, ZGC Life Sciences Park, Beijing, China
- Center for Quantitative Biology, School of Life Sciences, Peking University, Beijing, China
| | - Yu Xiao
- Hubei Key Laboratory of Urological Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China
- Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China
| | - Xinghuan Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China
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Zhao X, Qi X, Liu D, Che X, Wu G. A Novel Approach for Bladder Cancer Treatment: Nanoparticles as a Drug Delivery System. Int J Nanomedicine 2024; 19:13461-13483. [PMID: 39713223 PMCID: PMC11662911 DOI: 10.2147/ijn.s498729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 12/05/2024] [Indexed: 12/24/2024] Open
Abstract
Bladder cancer represents one of the most prevalent malignant neoplasms of the urinary tract. In the Asian context, it represents the eighth most common cancer in males. In 2022, there were approximately 613,791 individuals diagnosed with bladder cancer worldwide. Despite the availability of efficacious treatments for the two principal forms of bladder cancer, namely non-invasive and invasive bladder cancer, the high incidence of recurrence following treatment and the suboptimal outcomes observed in patients with high-grade and advanced disease represent significant concerns in the management of bladder cancer at this juncture. Nanoparticles have gained attention for their excellent properties, including stable physical properties, a porous structure that can be loaded with a variety of substances, and so on. The in-depth research on nanoparticles has led to their emergence as a new class of nanoparticles for combination therapy, due to their advantageous properties. These include the extension of the drug release window, the enhancement of drug bioavailability, the improvement of drug targeting ability, the reduction of local and systemic toxicity, and the simultaneous delivery of multiple drugs for combination therapy. As a result, nanoparticles have become a novel agent of the drug delivery system. The advent of nanoparticles has provided a new impetus for the development of non-surgical treatments for bladder cancer, including chemotherapy, immunotherapy, gene therapy and phototherapy. The unique properties of nanoparticles have facilitated the combination of diverse non-surgical therapeutic modalities, enhancing their overall efficacy. This review examines the recent advancements in the use of nanoparticles in non-surgical bladder cancer treatments, encompassing aspects such as delivery, therapeutic efficacy, and the associated toxicity of nanoparticles, as well as the challenges encountered in clinical applications.
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Affiliation(s)
- Xinming Zhao
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China
| | - Xiaochen Qi
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China
| | - Dequan Liu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China
| | - Xiangyu Che
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China
| | - Guangzhen Wu
- Department of Urology, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, People’s Republic of China
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Yin WJ, Huang YJ, Zhu Q, Lin XQ, Piao HL, Yu QQ, Lai CH, Zhou GL, Zhou LY, Liu K, Zuo XC, Zuo SR. Hypoalbuminemia and cisplatin-induced acute kidney injury. Front Pharmacol 2024; 15:1510477. [PMID: 39723253 PMCID: PMC11668559 DOI: 10.3389/fphar.2024.1510477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Accepted: 11/25/2024] [Indexed: 12/28/2024] Open
Abstract
Background Cisplatin binds to serum albumin in the body at a rate of 90%, and high levels of free cisplatin are a significant cause of its nephrotoxicity. Therefore, hypoalbuminemia theoretically poses a significant risk factor for cisplatin-induced acute kidney injury (CIA) and can be easily corrected. However, existing research results are inconsistent. Our aim is to confirm the association between hypoalbuminemia and CIA through a meta-analysis and a dual-center real-world data study. Methods First, we used a random-effects meta-analysis to summarize the odds ratio (OR) of the risk relationship between hypoalbuminemia and CIA. Then, we conducted a retrospective analysis of patients using cisplatin from Xiangya Third Hospital of Central South University (2014-2023) and Hunan Cancer Hospital (2019-2023) to analyze the relationship between hypoalbuminemia and CIA. Results The meta-analysis, which included six studies involving 4,359 cases, showed that hypoalbuminemia is associated with an increased risk of CIA (OR, 2.13; 95% CI, 1.37-3.32). A total of 5,452 and 25,214 patients from Xiangya Third Hospital and Hunan Cancer Hospital, respectively, were included. Both centers found a significant association between hypoalbuminemia and an increased risk of CIA (OR, 2.76; 95% CI, 1.94-3.93; OR, 2.88; 95% CI, 2.17-3.81), and the sensitivity analysis results were consistent. Conclusion Through meta-analysis and dual-center real-world data studies, we confirmed that hypoalbuminemia is an independent risk factor for CIA. Therefore, it is recommended that patients using cisplatin undergo serum albumin level testing and regular monitoring during treatment. Actively adjusting albumin levels may reduce the risk of CIA.
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Affiliation(s)
- Wen-Jun Yin
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yu-Jie Huang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qing Zhu
- Department of Pharmacy, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Xiao-Qing Lin
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hui-Ling Piao
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qian-Qian Yu
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chang-Hong Lai
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guang-Liang Zhou
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling-Yun Zhou
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Kun Liu
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiao-Cong Zuo
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shan-Ru Zuo
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Tsai TF, Hwang TIS, Chen PC, Chen YC, Chou KY, Ho CY, Chen HE, Chang AC. Hyperthermia reduces cancer cell invasion and combats chemoresistance and immune evasion in human bladder cancer. Int J Oncol 2024; 65:116. [PMID: 39513598 PMCID: PMC11575926 DOI: 10.3892/ijo.2024.5704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 09/19/2024] [Indexed: 11/15/2024] Open
Abstract
Bladder cancer (BC) is a common malignancy and its most prevalent type is urothelial carcinoma, which accounts for ~90% of all cases of BC. The current treatment options for BC are limited, which necessitates the development of alternative treatment strategies. Hyperthermia (HT), as an adjuvant cancer therapy, is known to improve the efficacy of chemotherapy or radiotherapy. The present study aimed to investigate the anti‑tumor effects of HT on cell survival, invasiveness, chemoresistance and immune evasion in human BC cell lines (5637, T24 and UMUC3). Calcein AM staining was performed to analyze the cytotoxicity of natural killer (NK) cells against human BC cells following HT treatment. Cell migration and invasion affected by HT were analyzed using Transwell migration and invasion assays. It was found that HT inhibited the proliferation of BC cells by downregulating the phosphorylation of protein kinase B. Moreover, HT effectively enhanced the sensitivity of BC cells to the chemotherapy drug cisplatin (DDP) and reduced the chemoresistance of DDP‑resistant cells by downregulating the expression of cadherin‑11. It was further demonstrated that HT inhibited the migration and invasion of BC cells and enhanced the cytotoxic effects of NK cells. In summary, the antineoplastic effects of HT were mediated through three main mechanisms: Enhancement of the chemosensitivity of BC cells and mitigation of DDP‑induced chemoresistance, suppression of the invasive potential of BC cells and reinforcement of the anticancer response of NK cells. Thus, HT appears to be a promising adjunctive therapy for human BC.
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Affiliation(s)
- Te-Fu Tsai
- Division of Urology, Department of Surgery, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111045, Taiwan, R.O.C
| | - Thomas I-Sheng Hwang
- Division of Urology, Department of Surgery, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111045, Taiwan, R.O.C
| | - Po-Chun Chen
- Department of Life Science, National Taiwan Normal University, Taipei 106308, Taiwan, R.O.C
| | - Yen-Chen Chen
- Translational Medicine Center, Research Department, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111045, Taiwan, R.O.C
| | - Kuang-Yu Chou
- Division of Urology, Department of Surgery, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111045, Taiwan, R.O.C
| | - Chao-Yen Ho
- Division of Urology, Department of Surgery, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111045, Taiwan, R.O.C
| | - Hung-En Chen
- Division of Urology, Department of Surgery, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111045, Taiwan, R.O.C
| | - An-Chen Chang
- Translational Medicine Center, Research Department, Shin Kong Wu Ho‑Su Memorial Hospital, Taipei 111045, Taiwan, R.O.C
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Li C, Yuan H, Chen J, Shang K, He H. The oncogenic functions of SPARCL1 in bladder cancer. J Cell Mol Med 2024; 28:e70196. [PMID: 39548034 PMCID: PMC11567778 DOI: 10.1111/jcmm.70196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 10/14/2024] [Accepted: 10/27/2024] [Indexed: 11/17/2024] Open
Abstract
Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) belongs to the SPARC family of matricellular proteins. However, underlying functions of SPARCL1 in bladder cancer (BCa) remain understudied. We performed an integrated search for the expression patterns of SPARCL1 in relation to various clinicopathological features of BCa. We then carried out Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and gene set enrichment analysis (GSEA). Furthermore, we investigated the correlations between SPARCL1 and immunological features, such as tumour mutation burden (TMB), immune activation processes, immune checkpoint expression, tumour immune dysfunction and exclusion (TIDE) scores, and chemotherapeutic sensitivity in BCa. Our analysis revealed that SPARCL1 was downregulated across multiple cancers. In BCa, elevated SPARCL1 was linked with advanced histopathologic stage, higher T and N stage, and poorer prognosis in the clinical cohort. In vitro experiments demonstrated that increased SPARCL1 expression inhibited cell proliferation, migration, and invasion. Additionally, highly expressed SPARCL1 was linked to elevated immune, stromal and ESTIMATE scores, as well as an increase in naive B cells, M2 macrophages, and resting mast cells. We observed a moderate correlation between SPARCL1 expression and CD163, VSIG4 and MS4A4A, which are markers of M2 macrophages. Furthermore, SPARCL1 expression was positively related to TMB, immune activation processes, TIDE scores, immune checkpoint expression, and chemotherapeutic sensitivity in BCa. Our study highlights the potential involvement of SPARCL1 in macrophage recruitment and polarization and suggests its utility as a biomarker for prognosis in BCa.
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Affiliation(s)
- Changjiu Li
- Department of Urology, Affiliated Hangzhou First People's HospitalWestlake University School of MedicineHangzhouChina
| | - Hui Yuan
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
- Department of UrologyNinghai First HospitalNingbo
| | - Jun Chen
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
| | - Kun Shang
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
| | - Huadong He
- Department of Urology, Affiliated Hangzhou First People's HospitalWestlake University School of MedicineHangzhouChina
- The Fourth Clinical Medical CollegeZhejiang Chinese Medical UniversityHangzhouChina
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Luo J, Luo F, Li Q, Liu Q, Wang J. An immunogenic cell death-related lncRNA signature correlates with prognosis and tumor immune microenvironment in bladder cancer. Sci Rep 2024; 14:13106. [PMID: 38849410 PMCID: PMC11161581 DOI: 10.1038/s41598-024-63852-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 06/03/2024] [Indexed: 06/09/2024] Open
Abstract
Immunogenic cell death (ICD) is a newly discovered form of cellular demise that triggers adaptive immune responses mediated by T cells. However, the immunogenic cell death-related lncRNAs (ICDRLs) involved in bladder cancer (BC) development and progression remain to be further elucidated. Molecular profiling data and clinicopathological information for BC patients were obtained from TCGA, and the ICDRGs list was obtained from published literature. For the identification of ICDRLs, Pearson co-expression analysis was performed, and a prognostic signature based on 13 ICDRLs was constructed by univariate assays and LASSO assays. Herein, an ICDRLSig consisting of 13 ICDRLs was constructed. KM curves and ROC curves demonstrated that the constructed signature in the TCGA training, testing, entire and external sets have good predictive performance. Multivariate assays illuminated that the signature is an independent predictor for BC patients' OS, exhibiting greater predictive power for the survival than traditional clinicopathological features. Additionally, patients in the high-ICDRLSig risk subgroup had more abundant immune infiltration, higher immune checkpoint gene expression, lower TMB and poorer response to immunotherapy. We have developed a novel ICDRLSig that can be exploited for survival prediction and provide a reference for further individualized treatment.
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Affiliation(s)
- Jinhong Luo
- Department of Oncology, East Hospital, Tongji University School of Medicine, No. 1800 Yuntai Road, Shanghai, 200123, China
- Department of Oncology, East Hospital, Ji'an Hospital, Ji'an, 343000, Jiangxi, China
| | - Feiye Luo
- Department of Urology, Dongfang People's Hospital, Dongfang, 572699, Hainan Province, China
| | - Qin Li
- Department of Oncology, East Hospital, Ji'an Hospital, Ji'an, 343000, Jiangxi, China
| | - Qinghong Liu
- Department of Oncology, East Hospital, Tongji University School of Medicine, No. 1800 Yuntai Road, Shanghai, 200123, China
| | - Jinshan Wang
- Department of Oncology, East Hospital, Tongji University School of Medicine, No. 1800 Yuntai Road, Shanghai, 200123, China.
- Department of Urology, Dongfang People's Hospital, Dongfang, 572699, Hainan Province, China.
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Pan G, Xie H, Xia Y. Disulfidptosis characterizes the tumor microenvironment and predicts immunotherapy sensitivity and prognosis in bladder cancer. Heliyon 2024; 10:e25573. [PMID: 38356551 PMCID: PMC10864973 DOI: 10.1016/j.heliyon.2024.e25573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 01/13/2024] [Accepted: 01/29/2024] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Bladder cancer (BLCA) is prone to metastasis and has poor prognosis with unsatisfactory treatment responsiveness. Disulfidptosis is a recently discovered, novel mode of cell death that is closely associated with human cancers. However, a comprehensive analysis of the relationship between disulfidptosis and BLCA is lacking. Therefore, this study aimed to explore the potential effect of disulfidptosis on BLCA and identify a biomarker for evaluating the prognosis and immunotherapy of patients with BLCA. MATERIAL AND METHODS We acquired BLCA RNA sequencing data from The Cancer Genome Atlas Urothelial Bladder Carcinoma (TCGA-BLCA) cohort (containing 19 normal samples and 409 tumor samples) and the GES39281 cohort (containing 94 tumor samples) which were used for external validation of the signature. Initially, we performed unsupervised consensus clustering to explore disulfidptosis-related subgroups. We then conducted functional enrichment analysis on these subgroups to gain insights into their biological significance and evaluate their immunotherapy response and chemotherapy sensitivity. Next, we conducted Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate Cox regression to construct a prognostic signature in the TCGA training set for prognosis-related differentially expressed genes (DEGs) in the disulfidptosis-related subgroups. Subsequently, we used a receiver operating characteristic (ROC) curve and independent prognostic analysis to validate the predictive performance of the signature in the TCGA testing and the GES39281 cohorts. Finally, we explored the therapeutic value of this signature in patients with BLCA, in terms of immunotherapy and chemotherapy. RESULT In this study, we obtained two subgroups: DRG-high (238 samples) and DRG-low (160 samples). The DRG-high group exhibited a poor survival rate compared to the DRG-low group and had a significant association with tumor grade, stage, and metastasis. Additionally, several pathways related to cancer and the immune system were enriched in the high-DRG group. Moreover, the DRG-high group exhibited higher expression of PD1 and CTLA4 and had a better response to immunotherapy in patients with both PD1 and CTLA4 positivity. Conversely, the DRG-high group was more sensitive to common chemotherapeutic agents. A prognostic signature was created, consisting of COL5A1, DIRAS3, NKG7, and POLR3G and validated as having a robust predictive capability. Patients in the low-risk-score group had more immune cells associated with tumor suppression and better immunotherapy outcomes. CONCLUSION This study contributes to our understanding of the characteristics of disulfidptosis-related subgroups in BLCA. Disulfidptosis-related signatures can be used to assess the prognosis and immunotherapy of patients with BLCA.
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Affiliation(s)
- Guizhen Pan
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Huan Xie
- Department of Urology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Yeye Xia
- Department of Radiation Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Department of Oncology, Chengdu Fifth People's Hospital, Sichuan, China
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Öztürk H, Karapolat İ. Evaluation of response to gemcitabine plus cisplatin-based chemotherapy using positron emission computed tomography for metastatic bladder cancer. World J Clin Cases 2023; 11:8447-8457. [PMID: 38188218 PMCID: PMC10768499 DOI: 10.12998/wjcc.v11.i36.8447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 11/10/2023] [Accepted: 12/06/2023] [Indexed: 12/22/2023] Open
Abstract
BACKGROUND The purpose of the present study was to examine retrospectively the contribution of 18Fluorodeoxyglucose positron emission tomography computed tomography (18FDG-PET/CT) to the evaluation of response to first-line gemcitabine plus cisplatin-based chemotherapy in patients with metastatic bladder cancer. AIM To evaluate the response to Gemcitabine plus Cisplatin -based chemotherapy using 18FDG-PET/CT imaging in patients with metastatic bladder cancer. METHODS Between July 2007 and April 2019, 79 patients underwent 18FDG-PET/CT imaging with the diagnosis of Metastatic Bladder Carcinoma (M-BCa). A total of 42 patients (38 male, 4 female) were included in the study, and all had been administered Gemcitabine plus Cisplatin-based chemotherapy. After completion of the therapy, the patients underwent a repeat 18FDG-PET/CT scan and the results were compared with the PET/CT findings before chemotherapy according to European Organisation for the Research and treatment of cancer criteria. Mean age was 66.1 years and standard deviation was 10.7 years (range: 41-84 years). RESULTS Of the patients, seven (16.6%) were in complete remission, 17 (40.5%) were in partial remission, six (14.3%) had a stable disease, and 12 (28.6%) had a progressive disease. The overall response rate was 57.1 percent. CONCLUSION 18FDG-PET/CT can be considered as a successful imaging tool in evaluating response to first-line chemotherapy for metastatic bladder cancer. Anatomical and functional data obtained from PET/CT scans may be useful in the planning of secondline and thirdline chemotherapy.
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Affiliation(s)
- Hakan Öztürk
- Department of Urology, Izmir University of Economics, Karsiyaka Izmir 35330, Turkey
| | - İnanç Karapolat
- Department of Nuclear Medicine, School of Medicine, İzmir Tınaztepe University, Izmir 35000, Turkey
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Mufti A, Feriani A, Ouchari W, Mandour YM, Tlili N, Ibrahim MA, Mahmoud MF, Sobeh M. Leonotis ocymifolia (Burm.f.) Iwarsson aerial parts aqueous extract mitigates cisplatin-induced nephrotoxicity via attenuation of inflammation, and DNA damage. Front Pharmacol 2023; 14:1221486. [PMID: 37593171 PMCID: PMC10428015 DOI: 10.3389/fphar.2023.1221486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 07/17/2023] [Indexed: 08/19/2023] Open
Abstract
Herein, we explored the protective effect of Leonotis ocymifolia (Burm.f.) Iwarsson aerial parts extract (LO) against cisplatin (CP)-induced nephrotoxicity in rats and profiled their phytocontents. A total of 31 compounds belonging to organic and phenolic acids and their glycosides as well as flavonoids and their O- and C-glycosides were identified through LC-MS/MS. The DPPH and FRAP assays revealed that the extract had powerful antioxidant properties. The in vivo results demonstrated that administering LO extract for 30 days (40 and 80 mg/kg b. w.) significantly improved the altered renal injury markers via reducing creatinine (high dose only) and uric acid levels compared to the Cp-group. The deleterious action of cisplatin on renal oxidative stress markers (GSH, MDA, SOD, and CAT) were also mitigated by LO-pretreatment. The reduction of the inflammatory marker (IL-6), and inhibition of DNA fragmentation, highlighted the prophylactic action of LO in kidney tissue. Molecular docking followed by a 100 ns molecular dynamic simulation analyses revealed that, amongst the 31 identified compounds in LO, chlorogenic and caffeoylmalic acids had the most stable binding to IL-6. The nephroprotective effects were further confirmed by histopathological observations, which showed improvement in ultrastructural changes induced by cisplatin. The observed findings reinforce the conclusion that L. ocymifolia extract exerts nephroprotective properties, which could be related to its antioxidant and anti-inflammatory activities. Further studies are required to determine the therapeutic doses and the proper administration time.
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Affiliation(s)
- Afoua Mufti
- Laboratory of Biotechnology and Biomonitoring of the Environment and Oasis Ecosystems, Faculty of Sciences of Gafsa, University of Gafsa, Gafsa, Tunisia
| | - Anouar Feriani
- Laboratory of Biotechnology and Biomonitoring of the Environment and Oasis Ecosystems, Faculty of Sciences of Gafsa, University of Gafsa, Gafsa, Tunisia
| | - Wafae Ouchari
- AgroBioSciences Program, College for Sustainable Agriculture and Environmental Science, Mohammed VI Polytechnic University, Ben Guerir, Morocco
| | - Yasmine M. Mandour
- School of Life and Medical Sciences, University of Hertfordshire Hosted By Global Academic Foundation, Cairo, Egypt
| | - Nizar Tlili
- Institut Supérieur des Sciences et Technologies de L’Environnement, Université de Carthage, Carthage, Tunisia
| | | | - Mona F. Mahmoud
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mansour Sobeh
- AgroBioSciences Program, College for Sustainable Agriculture and Environmental Science, Mohammed VI Polytechnic University, Ben Guerir, Morocco
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Nance RL, Sajib AM, Smith BF. Canine models of human cancer: Bridging the gap to improve precision medicine. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 189:67-99. [PMID: 35595353 DOI: 10.1016/bs.pmbts.2021.12.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Dogs are remarkable, adaptable, and dependable creatures that have evolved alongside humans while contributing tremendously to our survival. Our canine companions share many similarities to human disease, particularly cancer. With the advancement of next-generation sequencing technology, we are beginning to unravel the complexity of cancer and the vast intra- and intertumoral heterogeneity that makes treatment difficult. Consequently, precision medicine has emerged as a therapeutic approach to improve patient survival by evaluating and classifying an individual tumor's molecular profile. Many canine and human cancers share striking similarities in terms of genotypic, phenotypic, clinical, and histological presentations. Dogs are superior to rodent models of cancer because they are a naturally heterogeneous population in which tumors occur spontaneously, are exposed to similar environmental conditions, and show more similarities in key modulators of tumorigenesis and clinical response, including the immune system, drug metabolism, and gut microbiome. In this chapter, we will explore various canine models of human cancers and emphasize the dog's critical role in advancing precision medicine and improving the survival of both man and man's best friend.
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Affiliation(s)
- Rebecca L Nance
- Scott-Ritchey Research Center, Auburn University College of Veterinary Medicine, Auburn, AL, United States; Department of Pathobiology, Auburn University College of Veterinary Medicine, Auburn, AL, United States
| | - Abdul Mohin Sajib
- Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States
| | - Bruce F Smith
- Scott-Ritchey Research Center, Auburn University College of Veterinary Medicine, Auburn, AL, United States; Department of Pathobiology, Auburn University College of Veterinary Medicine, Auburn, AL, United States.
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Baicalein and Αlpha-Tocopherol Inhibit Toll-like Receptor Pathways in Cisplatin-Induced Nephrotoxicity. Molecules 2022; 27:molecules27072179. [PMID: 35408581 PMCID: PMC9000769 DOI: 10.3390/molecules27072179] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/13/2022] [Accepted: 03/14/2022] [Indexed: 02/05/2023] Open
Abstract
Cisplatin (CP) is a conventional chemotherapeutic agent with serious adverse effects. Its toxicity was linked to the stimulation of oxidative stress and inflammation. As a result, this study explored the protective effect of baicalein and alpha-tocopherol in nephrotoxicity induced by cisplatin. Until receiving an intraperitoneal injection of CP (3 mg/kg BW), rats were given baicalein orally 100 mg/kg for seven days or/and a single intraperitoneal injection of α-tocopherol 250 mg/kg. Renal function was tested to explore whether baicalein and α-tocopherol have any beneficial effects; blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) content, antioxidant activity biomarkers and histopathology of renal tissue, oxidative stress biomarkers, inflammatory response markers, and histopathological features of kidney architecture were measured. Cisplatin treatment resulted in extreme renal failure, as measured by high serum creatinine and BUN levels and severe renal changes. Cisplatin therapy resulted in increased lipid peroxidation and decreased glutathione and superoxide dismutase levels, reflecting oxidative stress. Upon treatment with α-tocopherol, baicalein, and combined therapy, there was augmentation in the antioxidant status as well as a reduction in IL-6, NF-κB, TNF, TLR2, and TLR4 and a significant increase in Keap-1 and NRF-2. The combined treatment was the most effective and the nearest to the normal status. These findings suggest that baicalein and α-tocopherol may be useful in preventing cisplatin-induced nephrotoxicity.
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12
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Intravenous Administration of Cisplatin with Magnesium Sulfate Supplement May Prevent Kidney Toxicity in Rats: The Role of Gender and Magnesium Sulfate Dose. Int J Nephrol 2022; 2022:1218222. [PMID: 35223098 PMCID: PMC8866029 DOI: 10.1155/2022/1218222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 01/22/2022] [Indexed: 11/17/2022] Open
Abstract
Background. Cisplatin (CP) is widely used to treat various kinds of malignancies, but to avoid its side effects of nephrotoxicity and hypomagnesemia, magnesium supplementation is a subject of debate. The current study was designed to determine the protective role of intravenous magnesium sulfate (MgSO4) against intravenous administration of CP in male and female rats. Method. In this case-control experimental study, 80 Wistar male and female rats in 12 groups of experiments were subjected to receive intravenous administration of CP accompanied with intravenous infusion of different doses (1, 3, and 10 mg/ml solution) of MgSO4 and were compared with the control groups. Results. CP administration increased blood urea nitrogen (BUN), creatinine (Cr), kidney tissue damage score (KTDS), and kidney weight (KW), and they were attenuated by the mid-dose of MgSO4 supplementation in female rats. However, in male rats, the increase of Cr, BUN, KTDS, and KW induced by CP was ameliorated by low, mid-, and high doses of MgSO4 supplements. The levels of these markers were significantly different between male and female rats in the mid-dose of MgSO4-treated group (BUN:
, Cr:
, KTDS:
, and KW:
). CP reduced clearance of Cr (ClCr) in both male and female rats significantly compared to the control group of saline alone (Pmale = 0.002 and Pfemale = 0.001), and the mid- and high doses of MgSO4 supplements improved ClCr in female rats. There were also sex differences in ClCr in mid- (
) and high (
) doses of MgSO4-treated groups. CP accompanied with the mid-dose of MgSO4 supplement reduced the KTDS (Pmale = 0.04 and Pfemale = 0.004) and KW (Pmale = 0.002 and Pfemale = 0.042) in both male and female rats significantly when compared with the CP-alone-treated group, while there were also significant differences between the sexes (KTDS:
and KW:
). CP accompanied with three different doses of MgSO4 supplements did not improve the serum levels of lactate dehydrogenase, urine level of sodium, malondialdehyde, urine flow, and nitrite statistically when compared with the CP-alone-treated group. Conclusion. The renal protective effect of MgSO4 could be dose and gender related.
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13
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Exploiting protein family and protein network data to identify novel drug targets for bladder cancer. Oncotarget 2022; 13:105-117. [PMID: 35035776 PMCID: PMC8758182 DOI: 10.18632/oncotarget.28175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022] Open
Abstract
Bladder cancer remains one of the most common forms of cancer and yet there are limited small molecule targeted therapies. Here, we present a computational platform to identify new potential targets for bladder cancer therapy. Our method initially exploited a set of known driver genes for bladder cancer combined with predicted bladder cancer genes from mutationally enriched protein domain families. We enriched this initial set of genes using protein network data to identify a comprehensive set of 323 putative bladder cancer targets. Pathway and cancer hallmarks analyses highlighted putative mechanisms in agreement with those previously reported for this cancer and revealed protein network modules highly enriched in potential drivers likely to be good targets for targeted therapies. 21 of our potential drug targets are targeted by FDA approved drugs for other diseases — some of them are known drivers or are already being targeted for bladder cancer (FGFR3, ERBB3, HDAC3, EGFR). A further 4 potential drug targets were identified by inheriting drug mappings across our in-house CATH domain functional families (FunFams). Our FunFam data also allowed us to identify drug targets in families that are less prone to side effects i.e., where structurally similar protein domain relatives are less dispersed across the human protein network. We provide information on our novel potential cancer driver genes, together with information on pathways, network modules and hallmarks associated with the predicted and known bladder cancer drivers and we highlight those drivers we predict to be likely drug targets.
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14
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Tan B, Chen J, Qin S, Liao C, Zhang Y, Wang D, Li S, Zhang Z, Zhang P, Xu F. Tryptophan Pathway-Targeted Metabolomics Study on the Mechanism and Intervention of Cisplatin-Induced Acute Kidney Injury in Rats. Chem Res Toxicol 2021; 34:1759-1768. [PMID: 34110802 DOI: 10.1021/acs.chemrestox.1c00110] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Cisplatin is a chemotherapeutic agent widely employed in the treatment of various solid tumors. However, its use is often restricted by acute kidney injury (AKI) which is the dose-limiting adverse effect of cisplatin. While numerous studies aiming to alleviate the AKI have been conducted, there are no effective remedies in clinical practice. In this paper, a targeted metabolomics study was performed to reveal the potential relationship between tryptophan metabolism and cisplatin-induced AKI. A chemical derivatization integrated liquid chromatography coupled tandem mass spectrometry (LC-MS/MS) approach was utilized to quantify 29 metabolites in the tryptophan pathway in rat kidney medulla and cortex after cisplatin administration. Results showed that tryptophan metabolism was remarkably disturbed both in the medulla and cortex after cisplatin administration. We also found that the tryptophan pathway in the medulla was more sensitive to cisplatin exposure compared with the cortex. Among these metabolites, indoxyl sulfate was focused for further study because it accumulated most significantly in the kidney cortex and medulla in a dose-dependent manner. A function verification study proved that chlormethiazole, a widely used CYP2E1 inhibitor, could reduce the production of indoxyl sulfate in the liver and attenuate cisplatin-induced AKI in rats. In conclusion, our study depicted the tryptophan pathway in cisplatin-induced AKI for the first time and demonstrated tryptophan metabolism is closely associated with the renal toxicity caused by cisplatin, which can be of great use for the discovery of renal toxicity attenuating remedies.
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Affiliation(s)
- Bei Tan
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Jie Chen
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Siyuan Qin
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Chuyao Liao
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Ying Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Di Wang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Siqi Li
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Zunjian Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Pei Zhang
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
| | - Fengguo Xu
- Key Laboratory of Drug Quality Control and Pharmacovigilance (Ministry of Education), State Key Laboratory of Natural Medicine, China Pharmaceutical University, Nanjing 210009, P.R. China
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15
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Final Overall Survival Analysis of the SOGUG Phase 2 MAJA Study: Maintenance Vinflunine Versus Best Supportive Care After First-Line Chemotherapy in Advanced Urothelial Carcinoma. Clin Genitourin Cancer 2020; 18:452-460. [DOI: 10.1016/j.clgc.2020.05.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/29/2020] [Accepted: 05/03/2020] [Indexed: 01/10/2023]
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16
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Sayed A, Munir M, Eweis N, Wael D, Shazly O, Awad AK, Elbadawy MA, Eissa S. An overview on precision therapy in bladder cancer. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1801346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Ahmed Sayed
- Faculty of Medicine, Undergraduate Medical Students, Ain Shams University, Cairo, Egypt
| | - Malak Munir
- Faculty of Medicine, Undergraduate Medical Students, Ain Shams University, Cairo, Egypt
| | - Noor Eweis
- Faculty of Medicine, Undergraduate Medical Students, Ain Shams University, Cairo, Egypt
| | - Doaa Wael
- Faculty of Medicine, Undergraduate Medical Students, Ain Shams University, Cairo, Egypt
| | - Omar Shazly
- Faculty of Medicine, Undergraduate Medical Students, Ain Shams University, Cairo, Egypt
| | - Ahmed K. Awad
- Faculty of Medicine, Undergraduate Medical Students, Ain Shams University, Cairo, Egypt
| | - Marihan A. Elbadawy
- Faculty of Medicine, Undergraduate Medical Students, Ain Shams University, Cairo, Egypt
| | - Sanaa Eissa
- Faculty of Medicine, Professor of Medical Biochemistry and Molecular Biology, Ain Shams University, Cairo, Egypt
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Ganoderma lucidum Prevents Cisplatin-Induced Nephrotoxicity through Inhibition of Epidermal Growth Factor Receptor Signaling and Autophagy-Mediated Apoptosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4932587. [PMID: 32695255 PMCID: PMC7362286 DOI: 10.1155/2020/4932587] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/16/2020] [Accepted: 06/02/2020] [Indexed: 01/07/2023]
Abstract
Background Cisplatin (cis-diaminedichloroplatinum, CDDP) is a broad-spectrum antineoplastic agent. However, CDDP has been blamed for its nephrotoxicity, which is the main dose-limiting adverse effect. Ganoderma lucidum (GL), a medicinal mushroom, has antioxidant and inflammatory activities. Therefore, this study is aimed at finding out the potential nephroprotection of GL against CDDP-induced nephrotoxicity in rats and the possible molecular mechanisms including the EGFR downstream signaling, apoptosis, and autophagy. Methods Rats were given GL (500 mg/kg) for 10 days and a single injection of CDDP (12 mg/kg, i.p). Results Nephrotoxicity was evidenced by a significant increase in renal indices and oxidative stress markers. Additionally, CDDP showed a plethora of inflammatory and apoptotic responses as evidenced by a profound increase of HMGB-1, NF-κB, and caspase-3 expressions, whereas administration of GL significantly improved all these indices as well as the histopathological insults. Renal expression of EGFR showed a similar trend after GL administration. Furthermore, activation of autophagy protein, LC3 II, was found to be involved in GL-mediated nephroprotection correlated with the downregulation of apoptotic signaling, caspase-3 and terminal deoxynucleotidyl transferase (TDT) renal expressions. Conclusion These results suggest that GL might have improved CDDP-induced nephrotoxicity through antioxidant, anti-inflammatory, and autophagy-mediated apoptosis mechanisms and that inhibition of EGFR signaling might be involved in nephroprotection.
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18
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Koźmiński P, Halik PK, Chesori R, Gniazdowska E. Overview of Dual-Acting Drug Methotrexate in Different Neurological Diseases, Autoimmune Pathologies and Cancers. Int J Mol Sci 2020; 21:ijms21103483. [PMID: 32423175 PMCID: PMC7279024 DOI: 10.3390/ijms21103483] [Citation(s) in RCA: 180] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 05/08/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
Methotrexate, a structural analogue of folic acid, is one of the most effective and extensively used drugs for treating many kinds of cancer or severe and resistant forms of autoimmune diseases. In this paper, we take an overview of the present state of knowledge with regards to complex mechanisms of methotrexate action and its applications as immunosuppressive drug or chemotherapeutic agent in oncological combination therapy. In addition, the issue of the potential benefits of methotrexate in the development of neurological disorders in Alzheimer’s disease or myasthenia gravis will be discussed.
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19
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New insights into the protection of growth hormone in cisplatin-induced nephrotoxicity: The impact of IGF-1 on the Keap1-Nrf2/HO-1 signaling. Life Sci 2020; 253:117581. [PMID: 32209424 DOI: 10.1016/j.lfs.2020.117581] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 03/17/2020] [Accepted: 03/19/2020] [Indexed: 12/30/2022]
Abstract
AIMS Cisplatin (CDDP) is an effective antineoplastic agent, however, its serious nephrotoxicity limits therapeutic use. Human growth hormone (hGH) has proved antioxidant and anti-inflammatory activities. The present study aimed to investigate the nephroprotective effects of hGH against CDDP-induced nephrotoxicity and the mechanisms underlying this nephroprotection. MAIN METHODS Male albino rats injected with CDDP (7 mg/kg) and nephrotoxicity indices, oxidative stress and inflammatory biomarkers (high mobility group box protein-1 (HMGB-1), soluble epoxide hydrolase (sEH), and nuclear factor-kappa B (NF-κB)) were assessed. Also, insulin-like growth factor-1 (IGF-1) and Nuclear factor-erythroid-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway were assessed. KEY FINDINGS hGH (1 mg/kg) improved kidney function and antioxidant systems and showed intact renal tubular epithelium. Cisplatin upregulated the HMGB-1/NF-κB and downregulated Nrf2/HO-1 pathways which were reversed by hGH and aligned with increased renal IGF-1 expression. Also, IGF-1/sEH crosstalk might be involved in hGH nephroprotection. Moreover, hGH downregulated HSP70 and caspase-3 expressions. SIGNIFICANCE these results concluded that hGH can attenuate the inflammation and oxidative stress attained by CDDP probably through inhibition of Nrf2/HO-1 pathway. We also suggested that Keap1/Nrf2-mediated upregulation of the antioxidant HO-1 might inhibit HMGB-1/NF-κB signaling and thus provide the principal protection mechanism offered by hGH against CDDP-induced kidney injury.
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20
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Qu HC, Huang Y, Mu ZY, Lv H, Xie QP, Wang K, Hu B. Efficacy and Safety of Chemotherapy Regimens in Advanced or Metastatic Bladder and Urothelial Carcinomas: An Updated Network Meta-Analysis. Front Pharmacol 2020; 10:1507. [PMID: 32009946 PMCID: PMC6974923 DOI: 10.3389/fphar.2019.01507] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Accepted: 11/20/2019] [Indexed: 11/13/2022] Open
Abstract
Background: Gemcitabine plus cisplatin (GC) and methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) have been the first-line treatments for advanced or metastatic urothelial carcinoma (AMUC). However, their effects are unsatisfactory, and more drugs and regimens still need to be explored. Objective: We aimed to comprehensively compare all possible regimens with GC or MVAC in randomized controlled trials (RCTs) by network meta-analysis. Methods: We searched the PubMed, Embase, and Cochrane databases for RCTs that evaluated regimens compared to GC or MVAC on AMUC patients. The major outcomes were progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). A network meta-analysis was used to assess the effectiveness and safety of the included treatment regimens, and the regimens were then clustered by the average linkage method. Results: A total of 19 trials that assessed 3,363 AMUC patients were included. For PFS, paclitaxel plus GC (PGC) was significantly superior to GC (log hazard ratio (HR): −0.16; 95% confidence interval (CI): −0.32, 0.00) with a moderate level of reliability. However, there was no significant difference between PGC and MVAC (log HR: −0.03; 95% CI: −0.27, 0.20). For OS, PGC was significantly superior to GC (log HR:−0.17; 95% CI: −0.33, −0.00) with a moderate reliability level but not significantly different from MVAC (log HR: −0.10; 95% CI: −0.35, 0.15). Analysis of ORR showed that PGC was superior to MVAC (log odds ratio (OR): 0.59; 95% CI: 0.02, 1.16) with a low reliability level and GC (log OR: 0.41; 95% CI: 0.12, 0.71) with a moderate reliability level. In the cluster results, PGC and sorafenib plus GC (GCS) exhibited relative advantages in efficiency, followed by MVAC and apatorsen plus GC (GCA); however, PGC, gemcitabine plus carboplatin (GP), and MVAC had more serious side effects. Conclusions: In our analysis, PGC was superior to MVAC and GC in only the ORR results and superior to GC in the OS and PFS results but was not significantly different from MVAC. More individualized therapies with targeted drugs need to be studied.
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Affiliation(s)
- Hong-Chen Qu
- Department of Urological Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Yan Huang
- Department of Urological Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Zhong-Yi Mu
- Department of Urological Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Hang Lv
- Department of Urological Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Qing-Peng Xie
- Department of Urological Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Kai Wang
- Department of Urological Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Bin Hu
- Department of Urological Surgery, Cancer Hospital of China Medical University/Liaoning Cancer Hospital & Institute, Shenyang, China
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21
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Knapp DW, Dhawan D, Ramos-Vara JA, Ratliff TL, Cresswell GM, Utturkar S, Sommer BC, Fulkerson CM, Hahn NM. Naturally-Occurring Invasive Urothelial Carcinoma in Dogs, a Unique Model to Drive Advances in Managing Muscle Invasive Bladder Cancer in Humans. Front Oncol 2020; 9:1493. [PMID: 32039002 PMCID: PMC6985458 DOI: 10.3389/fonc.2019.01493] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 12/11/2019] [Indexed: 12/11/2022] Open
Abstract
There is a great need to improve the outlook for people facing urinary bladder cancer, especially for patients with invasive urothelial carcinoma (InvUC) which is lethal in 50% of cases. Improved outcomes for patients with InvUC could come from advances on several fronts including emerging immunotherapies, targeted therapies, and new drug combinations; selection of patients most likely to respond to a given treatment based on molecular subtypes, immune signatures, and other characteristics; and prevention, early detection, and early intervention. Progress on all of these fronts will require clinically relevant animal models for translational research. The animal model(s) should possess key features that drive success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). Experimental animal models, while essential in bladder cancer research, do not possess these collective features to accurately predict outcomes in humans. These key features, however, are present in naturally-occurring InvUC in pet dogs. Canine InvUC closely mimics muscle-invasive bladder cancer in humans in cellular and molecular features, molecular subtypes, immune response patterns, biological behavior (sites and frequency of metastasis), and response to therapy. Thus, dogs can offer a highly relevant animal model to complement other models in research for new therapies for bladder cancer. Clinical treatment trials in pet dogs with InvUC are considered a win-win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. In addition, the high breed-associated risk for InvUC in dogs (e.g., 20-fold increased risk in Scottish Terriers) offers an unparalleled opportunity to test new strategies in primary prevention, early detection, and early intervention. This review will provide an overview of canine InvUC, summarize the similarities (and differences) between canine and human InvUC, and provide evidence for the expanding value of this canine model in bladder cancer research.
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Affiliation(s)
- Deborah W Knapp
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, United States.,Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States
| | - Deepika Dhawan
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, United States
| | - José A Ramos-Vara
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States.,Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| | - Timothy L Ratliff
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States.,Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, United States
| | - Gregory M Cresswell
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States
| | - Sagar Utturkar
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States
| | - Breann C Sommer
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, United States
| | - Christopher M Fulkerson
- Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, United States.,Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN, United States
| | - Noah M Hahn
- Department of Oncology and Urology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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22
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The Predictive Role of the Biomarker Kidney Molecule-1 (KIM-1) in Acute Kidney Injury (AKI) Cisplatin-Induced Nephrotoxicity. Int J Mol Sci 2019; 20:ijms20205238. [PMID: 31652595 PMCID: PMC6834366 DOI: 10.3390/ijms20205238] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/09/2019] [Accepted: 10/17/2019] [Indexed: 12/14/2022] Open
Abstract
Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cisplatin-induced renal injury both in vitro and in vivo studies. In this review, we focus on describing the mechanisms of renal tubular cells cisplatin-induced apoptosis, the associated inflammatory response and oxidative stress and the role of KIM-1 as a possible biomarker used to predict cisplatin associated AKI.
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23
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Huang CP, Chen J, Chen CC, Liu G, Zhang Y, Messing E, Yeh S, Chang C. ASC-J9® increases the bladder cancer chemotherapy efficacy via altering the androgen receptor (AR) and NF-κB survival signals. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:275. [PMID: 31234917 PMCID: PMC6592003 DOI: 10.1186/s13046-019-1258-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Accepted: 05/31/2019] [Indexed: 01/02/2023]
Abstract
Background The current chemotherapy regimens may extend survival for patients with metastatic bladder cancer (BCa) for a few months, but eventually most patients succumb to disease because they develop resistance to their chemotherapy. Methods TCGA human clinical sample survey and urothelial tumor tissue microarrays (TMAs) were applied to investigate the expression of androgen receptor (AR) and NF-κB. Multiple BCa cell lines were used to test chemotherapy’s efficacy via multiple assays including XTT, flow cytometry, TUNEL, and BrdU incorporation. The effects of the AR degradation enhancer, ASC-J9®, combined with various chemotherapy reagents were examined both in vivo and in vitro. Results We unexpectedly found that in muscle-invasive BCa (miBCa) the signals of both the AR and NF-κB were increased via a TCGA sample survey. Results from multiple approaches revealed that targeting these two increased signals by combining various chemotherapeutic agents, including Cisplatin, Doxorubicin or Mitomycin C, with ASC-J9® led to increase the therapeutic efficacy. The combined therapy increases the expression of the pro-apoptosis BAX gene and cell cycle inhibitor p21 gene, yet suppresses the expression of the pro-survival BCL2 gene in miBCa cells. Preclinical studies using an in vivo mouse model with xenografted miBCa cells confirmed in vitro cell line data showing that treatment with ASC-J9® combined with Cisplatin can result in suppressing miBCa progression better than Cisplatin alone. Conclusions Together, these results support a novel therapeutic approach via combining Cisplatin with ASC-J9® to better suppress the progression of miBCa. Electronic supplementary material The online version of this article (10.1186/s13046-019-1258-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Chi-Ping Huang
- Sex Hormone Research Center and Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan
| | - Jinbo Chen
- Department of Urology, Xiangya Hospital, Central South University, Changsha, 410008, China.,George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Chi-Cheng Chen
- Sex Hormone Research Center and Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan.,Department of Urology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, 404, Taiwan
| | - Guodong Liu
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Yong Zhang
- Department of Urology, the Second Hospital of Hebei Medical University, Shijiazhuang, 050000, China
| | - Edward Messing
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Shuyuan Yeh
- George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA
| | - Chawnshang Chang
- Sex Hormone Research Center and Department of Urology, China Medical University/Hospital, Taichung, 404, Taiwan. .,George Whipple Lab for Cancer Research, Departments of Pathology, Urology, Radiation Oncology and The Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.
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24
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Volarevic V, Djokovic B, Jankovic MG, Harrell CR, Fellabaum C, Djonov V, Arsenijevic N. Molecular mechanisms of cisplatin-induced nephrotoxicity: a balance on the knife edge between renoprotection and tumor toxicity. J Biomed Sci 2019; 26:25. [PMID: 30866950 PMCID: PMC6417243 DOI: 10.1186/s12929-019-0518-9] [Citation(s) in RCA: 307] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Accepted: 03/07/2019] [Indexed: 12/15/2022] Open
Abstract
Background Cisplatin (cis-diamminedichloroplatinum II, CDDP) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe side effects, including nephrotoxicity and acute kidney injury (AKI) which develop due to renal accumulation and biotransformation of CDDP. The alleviation or prevention of CDDP-caused nephrotoxicity is currently accomplished by hydration, magnesium supplementation or mannitol-induced forced diuresis which is considered for high-dose CDDP-treated patients. However, mannitol treatment causes over-diuresis and consequent dehydration in CDDP-treated patients, indicating an urgent need for the clinical use of safe and efficacious renoprotective drug as an additive therapy for high dose CDDP-treated patients. Main body In this review article we describe in detail signaling pathways involved in CDDP-induced apoptosis of renal tubular cells, oxidative stress and inflammatory response in injured kidneys in order to pave the way for the design of new therapeutic approaches that can minimize CDDP-induced nephrotoxicity. Most of these molecular pathways are, at the same time, crucially involved in cytotoxic activity of CDDP against tumor cells and potential alterations in their function might mitigate CDDP-induced anti-tumor effects. Conclusion Despite the fact that many molecules were designated as potential therapeutic targets for renoprotection against CDDP, modulation of CDDP-induced nephrotoxicity still represents a balance on the knife edge between renoprotection and tumor toxicity.
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Affiliation(s)
- Vladislav Volarevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, Kragujevac, 34000, Serbia.
| | - Bojana Djokovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, Kragujevac, 34000, Serbia
| | - Marina Gazdic Jankovic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - C Randall Harrell
- Regenerative Processing Plant, LLC, US Highway 19 N Palm Harbor, Palm Harbor, Florida, 34176, USA
| | - Crissy Fellabaum
- Regenerative Processing Plant, LLC, US Highway 19 N Palm Harbor, Palm Harbor, Florida, 34176, USA
| | - Valentin Djonov
- Institute of Anatomy, University of Bern, 2 Baltzerstrasse, Bern, Switzerland
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, Kragujevac, 34000, Serbia
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Huang C, Zhou W, Song P, Yuan N. Comparison of different prognostic models for predicting cancer-specific survival in bladder transitional cell carcinoma. Future Oncol 2019; 15:851-864. [PMID: 30657341 DOI: 10.2217/fon-2018-0695] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE To construct the newly valuable nomogram which can compare the predictive performance with American Joint Committee on Cancer (AJCC) staging system in bladder transitional cell carcinoma (BTCC). METHODS BTCC patients were screened (2004-2015) from the SEER database. The nomogram incorporating lymph node ratio was constructed to evaluate individualized cancer-specific survival. RESULTS The C-index of the nomogram for predicting cancer-specific survival was 0.743 (95% CI: 0.720-0.766), which was higher than C-index of the AJCC staging system. CONCLUSION Lymph node ratio can be a reliable prognostic indicator for BTCC. The proposed nomogram showed more satisfactory predictive accuracy and wider applicability than current AJCC staging system in individualized prediction of BTCC patients.
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Affiliation(s)
- ChuiGuo Huang
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, Henan Province, PR China
| | - WeiWen Zhou
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, Guangdong Province, PR China
| | - Pan Song
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, Henan Province, PR China
| | - NaiJun Yuan
- The School of Traditional Chinese Medicine of Jinan University, Guangzhou 510632, Guangdong Province, PR China
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Li C, Wang Z, Feng N, Dong J, Deng X, Yue Y, Guo Y, Hou J. Human HLA‑F adjacent transcript 10 promotes the formation of cancer initiating cells and cisplatin resistance in bladder cancer. Mol Med Rep 2018; 18:308-314. [PMID: 29749526 PMCID: PMC6059684 DOI: 10.3892/mmr.2018.9005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2017] [Accepted: 04/16/2018] [Indexed: 01/01/2023] Open
Abstract
Epithelial to mesenchymal transition (EMT) serves important roles in tumor invasion, metastasis, formation of cancer initiating cells (CICs) and drug resistance. HLA‑F adjacent transcript 10 (FAT10) has been proposed as an oncogene in bladder cancer. However, the functional contribution of FAT10 to EMT and the formation of CICs remains unclear in bladder cancer. The present study reports that FAT10 protein expression is upregulated in bladder cancer cell lines, and the overexpression of FAT10 promotes EMT and the formation of CICs in bladder cancer UMUC‑3 cells. In addition, increased expression of FAT10 in tumor tissue was associated with shorter overall survival and progression free survival in Chinese patients with bladder cancer. Overexpression of FAT10 promotes cisplatin‑resistant bladder cancer formation. These results indicated FAT10 may be a novel target for the treatment of bladder cancer.
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Affiliation(s)
- Chen Li
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
- Department of Urology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Zhenfan Wang
- Department of Urology, The First Hospital of Wujiang, Suzhou, Jiangsu 215200, P.R. China
| | - Ninghan Feng
- Department of Urology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Jian Dong
- Department of Urology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Xiaoyan Deng
- Department of Urology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Yin Yue
- Department of Urology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Yuehong Guo
- Department of Urology, Nanjing Medical University Affiliated Wuxi Second Hospital, Wuxi, Jiangsu 214002, P.R. China
| | - Jianquan Hou
- Department of Urology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, P.R. China
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Kim MJ, Kim YS, Oh SY, Lee S, Choi YJ, Seol YM, Park MJ, Kim KH, Park LC, Kang JH, Hwang IG, Lee SI, Lim ST, Kim HS, Lim HY, Rha SY, Kim HJ. Retrospective analysis of palliative chemotherapy for the patients with bladder adenocarcinoma: Korean Cancer Study Group Genitourinary and Gynecology Cancer Committee. Korean J Intern Med 2018; 33:383-390. [PMID: 27048257 PMCID: PMC5840579 DOI: 10.3904/kjim.2015.162] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 12/12/2015] [Accepted: 12/31/2015] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND/AIMS Because of rarity, role of chemotherapy of bladder adenocarcinoma are still unidentified. Therefore, we performed a retrospective analysis of the clinical features and chemotherapy outcomes of bladder adenocarcinoma. METHODS Eligible patients for this retrospective analysis were initially diagnosed with bladder adenocarcinoma and presented with a clinically no other primary site of origin. The collected data included age, gender, performance status, stage, hemoglobin, albumin, initial date of diagnosis, treatment modality utilized, response to treatment, presence of relapse, last status of patient, and last date of follow-up. RESULTS We retrospectively reviewed 29 patients, who were treated with chemotherapy for bladder adenocarcinoma at 10 Korean medical institutions from 2004 to 2014. The median age of patients was 58 years (range, 17 to 78) and 51.7% of the patients were female. Urachal adenocarcinoma was identified in 15 patients. Of 27 symptomatic patients, 22 experienced gross hematuria. Twelve patients were treated with 5-f luorouracil based chemotherapy, five were gemcitabine based, three were taxane and others. Thirteen of them achieved complete response (10.3%) or partial response (34.5%). Median progression-free survival (PFS) and overall survival (OS) for all patients were 10.6 months (95% confidence interval [CI], 9.5 to 11.6) and 24.5 months (95% CI, 1.2 to 47.8), respectively. The cases of urachal adenocarcinoma exhibited worse tendency in PFS and OS (p = 0.024 and p = 0.046, respectively). CONCLUSIONS Even though bladder adenocarcinoma had been observed moderate effectiveness to chemotherapy, bladder adenocarcinoma is a highly aggressive form of bladder cancer. PFS and OS were short especially in urachal carcinoma.
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Affiliation(s)
- Moon Jin Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - Sung Yong Oh
- Dong-A University Hospital, Busan, Korea
- Correspondence to Sung Yong Oh, M.D. Department of Internal Medicine, Dong-A University Hospital, 26 Daesingongwon-ro, Seo-gu, Busan 49201, Korea Tel: +82-51-240-2808 Fax: +82-51-246-5044 E-mail:
| | - Suee Lee
- Dong-A University Hospital, Busan, Korea
| | | | | | - Min Jae Park
- Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Ki Hyang Kim
- Inje University Busan Paik Hospital, Busan, Korea
| | | | - Jung Hun Kang
- Gyeongsang National University Hospital, Jinju, Korea
| | - In-Gyu Hwang
- Chung-Ang University College of Medicine, Seoul, Korea
| | - Soon Il Lee
- Dankook University College of Medicine, Cheonan, Korea
| | | | - Hyo Song Kim
- Yonsei University College of Medicine, Seoul, Korea
| | - Ho Yeong Lim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Intravenous injections of the oncolytic virus M1 as a novel therapy for muscle-invasive bladder cancer. Cell Death Dis 2018; 9:274. [PMID: 29449555 PMCID: PMC5833719 DOI: 10.1038/s41419-018-0325-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 01/16/2018] [Accepted: 01/17/2018] [Indexed: 12/11/2022]
Abstract
Muscle-invasive bladder cancer (MIBC) is associated with low survival and high recurrence rates even in cases in which patients receive systemic treatments, such as surgery and chemotherapy. Here, we found that a naturally existing alphavirus, namely, M1, selectively kills bladder cancer cells but not normal cells, findings supported by our observations of changes in viral replication and MIBC and patient-derived MIBC cell apoptosis. Transcriptome analysis revealed that interferon-stimulated genes (ISGs) are expressed at low levels in sensitive bladder cancer cells and high levels in resistant cells. Knocking down ZC3HAV1 (ZAP), an antiviral factor in ISGs, restores M1 virus reactivity in resistant cells, and overexpressing ZAP partially reverses M1 virus-induced decreases in cell viability in sensitive cells. In orthotopic MIBC mice, tail vein injections of M1 significant inhibit tumor growth and prolong survival period, antitumor effects of M1 are stronger than those of the first-line chemotherapy agent cisplatin (CDDP). Treated tumors display enhanced cleaved-caspase-3 signals, which are representative of cell apoptosis, and decreased Ki-67 signals, which are representative of cell proliferation. Moreover, tissue microarray (TMA) analyses of clinical tumor specimens revealed that up to 45.6% of cases of MIBC presented with low ZAP expression, a finding that is prevalent in advanced MIBC. Our results indicate that the oncolytic virus M1 is a novel agent capable of functioning as a precise and effective therapy for MIBC.
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29
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Loh JM, Tran AL, Ji L, Groshen S, Daneshmand S, Schuckman A, Quinn DI, Dorff TB. Baseline Glomerular Filtration Rate and Cisplatin- Induced Renal Toxicity in Urothelial Cancer Patients. Clin Genitourin Cancer 2017; 16:S1558-7673(17)30271-9. [PMID: 28958673 PMCID: PMC7515775 DOI: 10.1016/j.clgc.2017.08.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Revised: 08/17/2017] [Accepted: 08/28/2017] [Indexed: 11/23/2022]
Abstract
BACKGROUND Cisplatin eligibility for clinical trials has been defined as glomerular filtration rate (GFR) ≥ 60 mL/min due to the risk of nephrotoxicity in patients with renal impairment. For urothelial cancer, substitution of carboplatin instead of cisplatin compromises outcomes. We evaluated change in GFR in patients treated with cisplatin despite baseline GFR < 60 mL/min to determine risk of nephrotoxicity. PATIENTS AND METHODS Patients treated between 2009 and 2014 at our institution were identified by the institutional review board-approved cystectomy database. GFR percentage change was compared by age (< 75 vs. ≥ 75 years), pretreatment GFR (< 60 vs. ≥ 60 mL/min), therapy setting (neoadjuvant, adjuvant, or metastatic), primary disease site, and comorbidities (diabetes, hypertension, and hyperlipidemia). The associations between overall survival and age or GFR were also assessed. RESULTS There were 81 patients who received cisplatin-based therapy and whose pre- and posttreatment GFR were available. Median GFR change was -1.6% for patients with pretreatment GFR < 60 mL/min compared to -10.9% for patients with pretreatment GFR ≥ 60 mL/min (P = .17). Therapy setting was the only factor in our study to be significantly associated with GFR change (P = .027). No association was found between overall survival and pre- or posttreatment GFR, GFR percentage change, or age. CONCLUSION Our data support the hypothesis that urothelial cancer patients with GFR < 60 mL/min do not experience a greater decline in renal function after cisplatin compared to patients with GFR ≥ 60 mL/min. If validated, this may extend the option of cisplatin-based therapy to previously ineligible patients.
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Affiliation(s)
- Janice M Loh
- Keck School of Medicine of the University of Southern California, Los Angeles, CA
| | - Adrienne L Tran
- Keck School of Medicine of the University of Southern California, Los Angeles, CA
| | - Lingyun Ji
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA
| | - Susan Groshen
- Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, CA
| | - Siamak Daneshmand
- Institute of Urology, USC Norris Comprehensive Cancer Center, Los Angeles, CA
| | - Anne Schuckman
- Institute of Urology, USC Norris Comprehensive Cancer Center, Los Angeles, CA
| | - David I Quinn
- Keck School of Medicine, Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, CA
| | - Tanya B Dorff
- Keck School of Medicine, Division of Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, CA.
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Liu T, Li L, Yin L, Yu H, Jing H, Liu Y, Kong C, Xu M. Superantigen staphylococcal enterotoxin C1 inhibits the growth of bladder cancer. Biosci Biotechnol Biochem 2017; 81:1741-1746. [PMID: 28715277 DOI: 10.1080/09168451.2017.1350564] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Abstract
Superantigens can induce cell-mediated cytotoxicity preferentially against MHC II-positive target cells with large amounts of inflammatory cytokines releasing. In this study, superantigen staphylococcal enterotoxin C (SEC) 1 was investigated to evaluate its potential in bladder cancer immunotherapy in vitro and in vivo. Our results revealed that SEC1 could stimulate the proliferation of human peripheral blood mononuclear cells (PBMCs) in a dose-dependent manner, accompanied with the release of interleukin-2, interferon-γ, and tumor necrosis factor-α, and increased the population of CD4+ T cells and CD8+ T cells. PBMCs stimulated by SEC1 could initiate significant cytotoxicity towards human bladder cancer cells in vitro. The results of in vivo antitumor experiment indicated that SEC1 could decrease the rate of tumor formation and prolong the survival time of tumor-bearing mice. Our study demonstrated that SEC1 inhibited the growth of bladder cancer. And it is also suggested that SEC1 may become a candidate for bladder cancer immunotherapy.
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Affiliation(s)
- Tao Liu
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Lin Li
- Department of Rehabilitation Medicine, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Lei Yin
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Hongyuan Yu
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Hongwei Jing
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Yang Liu
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Chuize Kong
- Department of Urology, The First Affiliated Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Mingkai Xu
- Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang, People’s Republic of China
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Kuş T, Aktaş G. Maintenance treatment with gemcitabine have a promising activity on metastatic bladder cancer survival. Turk J Urol 2017; 43:273-278. [PMID: 28861297 DOI: 10.5152/tud.2017.24478] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 02/06/2017] [Indexed: 01/04/2023]
Abstract
OBJECTIVE To investigate the effects of gemcitabine maintenance treatment on survival in patients with metastatic bladder cancer. MATERIAL AND METHODS Gemcitabine maintenance monotherapy was administered following the standard platinum-gemcitabine therapy in patients with metastatic bladder cancer. Patients who had responded to standard treatment received maintenance gemcitabine therapy as 1000 mg/m2 on days 1 and 8 every three weeks until progression or development of unacceptable toxicity. The following clinical factors were noted: performance status, age, sex, stage, site of metastasis, choice of cisplatin-gemcitabine or carboplatin-gemcitabine, response rates to the initial chemotherapy. Progression-free survival (PFS) and overall survival (OS) for standard treatment, and following gemcitabine monotreatment and for maintenance gemcitabine therapy were calculated using Kaplan-Meier method. RESULTS A total of 88 patients with metastatic bladder cancer treated between February 2009 to October 2015 were evaluated retrospectively and 23 patients (26.1%) who had responded to six cycles of platinum-gemcitabine treatment were included in this study. Maintenance gamcitabine was administered for a median of 7 times (range 3-14 times). Grade 3 hematotoxicity according to the criteria of the Common Terminology Criteria of Adverse Events was observed in 7 (30.4%) patients. Median PFS of patients was 46 (range: 30-82) weeks for platinum-based treatment plus maintenance gemcitabine therapy. A higher median PFS was obtained in patients who were <65 year-olds, without organ metastasis with objective response rate, however, it was statistically insignificant. CONCLUSION Gemcitabine maintenance therapy in metastatic bladder cancer patients who did not shown progression after the standard platinum-gemcitabine treatment contributes to survival and presents low toxicity profile, when compared to historical controls.
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Affiliation(s)
- Tülay Kuş
- Department of Medical Oncology, Gaziantep University School of Medicine, Gaziantep, Turkey
| | - Gökmen Aktaş
- Department of Medical Oncology, Gaziantep University School of Medicine, Gaziantep, Turkey
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Maintenance therapy with vinflunine plus best supportive care versus best supportive care alone in patients with advanced urothelial carcinoma with a response after first-line chemotherapy (MAJA; SOGUG 2011/02): a multicentre, randomised, controlled, open-label, phase 2 trial. Lancet Oncol 2017; 18:672-681a. [DOI: 10.1016/s1470-2045(17)30242-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/17/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023]
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Li X, Liu S. Suppression of HBXIP Reduces Cell Proliferation, Migration and InvasionIn Vitro, and TumorigenesisIn Vivoin Human Urothelial Carcinoma of the Bladder. Cancer Biother Radiopharm 2016; 31:311-316. [PMID: 27831760 DOI: 10.1089/cbr.2016.2038] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Affiliation(s)
- Xiaogang Li
- Department of Urology, The Affiliated Hospital of YanBian University, Yanbian, China
| | - Shuangping Liu
- Department of Pathology, YanBian University, Yanbian, China
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Martel-Frachet V, Keramidas M, Nurisso A, DeBonis S, Rome C, Coll JL, Boumendjel A, Skoufias DA, Ronot X. IPP51, a chalcone acting as a microtubule inhibitor with in vivo antitumor activity against bladder carcinoma. Oncotarget 2016; 6:14669-86. [PMID: 26036640 PMCID: PMC4546496 DOI: 10.18632/oncotarget.4144] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Accepted: 04/08/2015] [Indexed: 12/18/2022] Open
Abstract
We previously identified 1-(2,4-dimethoxyphenyl)-3-(1-methylindolyl) propenone (IPP51), a new chalcone derivative that is capable of inducing prometaphase arrest and subsequent apoptosis of bladder cancer cells. Here, we demonstrate that IPP51 selectively inhibits proliferation of tumor-derived cells versus normal non-tumor cells. IPP51 interfered with spindle formation and mitotic chromosome alignment. Accumulation of cyclin B1 and mitotic checkpoint proteins Bub1 and BubR1 on chromosomes in IPP51 treated cells indicated the activation of spindle-assembly checkpoint, which is consistent with the mitotic arrest. The antimitotic actions of other chalcones are often associated with microtubule disruption. Indeed, IPP51 inhibited tubulin polymerization in an in vitro assay with purified tubulin. In cells, IPP51 induced an increase in soluble tubulin. Furthermore, IPP51 inhibited in vitro capillary-like tube formation by endothelial cells, indicating that it has anti-angiogenic activity. Molecular docking showed that the indol group of IPP51 can be accommodated in the colchicine binding site of tubulin. This characteristic was confirmed by an in vitro competition assay demonstrating that IPP51 can compete for colchicine binding to soluble tubulin. Finally, in a human bladder xenograft mouse model, IPP51 inhibited tumor growth without signs of toxicity. Altogether, these findings suggest that IPP51 is an attractive new microtubule-targeting agent with potential chemotherapeutic value.
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Affiliation(s)
- Véronique Martel-Frachet
- Université Joseph Fourier, AGIM CNRS FRE, EPHE, GRENOBLE Cedex 9. Université Joseph Fourier, Grenoble, France
| | - Michelle Keramidas
- Unité INSERM/UJF U823, Centre de recherche Albert Bonniot, Grenoble, France
| | - Alessandra Nurisso
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Quai Ernest-Ansermet, Geneva, Switzerland
| | | | - Claire Rome
- Unité Inserm, Grenoble Institute of Neuroscience, Site Santé, Grenoble, France
| | - Jean-Luc Coll
- Unité INSERM/UJF U823, Centre de recherche Albert Bonniot, Grenoble, France
| | - Ahcène Boumendjel
- Université de Grenoble/CNRS, UMR, Département de Pharmacochimie Moléculaire, Grenoble Cedex, France
| | | | - Xavier Ronot
- Université Joseph Fourier, AGIM CNRS FRE, EPHE, GRENOBLE Cedex 9. Université Joseph Fourier, Grenoble, France
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Oliveira PA, Gil da Costa RM, Vasconcelos-Nóbrega C, Arantes-Rodrigues R, Pinto-Leite R. Challenges within vitroandin vivoexperimental models of urinary bladder cancer for novel drug discovery. Expert Opin Drug Discov 2016; 11:599-607. [DOI: 10.1080/17460441.2016.1174690] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Zhang MN, Ding Z, Long YT. Sensing cisplatin-induced permeation of single live human bladder cancer cells by scanning electrochemical microscopy. Analyst 2016; 140:6054-60. [PMID: 26194058 DOI: 10.1039/c5an01148e] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Cisplatin is a widely used anti-cancer agent, which was believed to trigger apoptosis of cancer cells by forming DNA adducts. However, recent studies evidenced a cisplatin-induced extrinsic apoptotic pathway through interaction with plasma membranes. We present quantitative time-course imaging of cisplatin-induced permeation of ferrocenemethanol to single live human bladder cancer cells (T24) using scanning electrochemical microscopy (SECM). Simultaneous quantification of cellular topography and membrane permeability was realized by running SECM in the depth scan mode. It was demonstrated that the acute addition of cisplatin to the outer environment of T24 cells immediately induced membrane permeability change in 5 min, which indicated a loosened structure of the cellular membrane upon cisplatin dosage. The cisplatin-induced permeation of T24 cells might be a one-step action, an extrinsic mechanism, since the cell response was quick, and no continuous increase in the membrane permeability was observed. The time-lapse SECM depth scan method provided a simple and facile way of monitoring cisplatin-induced membrane permeability changes. Our study is anticipated to lead to a methodology of screening anti-cancer drugs through their interactions with live cells.
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Affiliation(s)
- Meng-Ni Zhang
- Department of Chemistry, The University of Western Ontario, London, ON, Canada N6A 5B7.
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RADIATION THERAPY OF A PRESUMPTIVE URETHRAL TRANSITIONAL CELL CARCINOMA IN AN EASTERN GRAY SQUIRREL (SCIURUS CAROLINENSIS). J Zoo Wildl Med 2015; 46:918-20. [PMID: 26667551 DOI: 10.1638/2013-0084.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
An adult female Eastern gray squirrel (Sciurus carolinensis), with a previous history of primary renal transitional cell carcinoma treated by nephrectomy, was diagnosed with a metastatic urethral transitional cell carcinoma (TCC) utilizing the veterinary bladder tumor antigen test in combination with other noninvasive diagnostic tests. The squirrel was treated with piroxicam and external beam radiation therapy given in 18 treatments over 30 days to achieve a total of 54 gray. Mild to moderate side effects from the pelvic irradiation were self-limiting and easily managed. Resolution of clinical signs was achieved for approximately 6 mo until recurrence of metastasis. This report represents the first published account of both TCC and external beam radiation therapy in an Eastern gray squirrel.
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Song T, Zhang X, Yang G, Song Y, Cai W. Decrement of miR-199a-5p contributes to the tumorigenesis of bladder urothelial carcinoma by regulating MLK3/NF-κB pathway. Am J Transl Res 2015; 7:2786-2794. [PMID: 26885275 PMCID: PMC4731675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 08/18/2015] [Indexed: 06/05/2023]
Abstract
Aberrant miRNA expression is implicated in tumorigenesis. However, the role of miRNAs in bladder urothelial carcinoma still remains largely unknown. In this study, miR-199a-5p was validated to be significantly down-regulated in bladder urothelial carcinoma. In addition, restoring expression of miR-199a-5p inhibited the tumorigenesis of bladder urothelial carcinoma in vitro and in vivo by inducing the apoptosis and suppressing the proliferation of bladder cancerous cells. Further investigation reported that MLK3 was a direct target of miR-199a-5p. Moreover, the expression level of miR-199a-5p was conversely correlated with MLK3 in bladder cancerous cells. In addition, reintroduction of MLK3 was identified to promote the proliferation and inhibit the apoptotic rate of cells, which have been altered by miR-199a-5p through activating the NF-κB pathway. All together, decrement of miR-199a-5p contributes to the tumorigenesis of bladder cancer by directly regulating MLK3/NF-κB pathway and miR-199a-5p might be developed as a therapeutic target for treatment of the bladder urothelial carcinoma.
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Affiliation(s)
- Tao Song
- Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital Beijing 100853, China
| | - Xu Zhang
- Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital Beijing 100853, China
| | - Guoqiang Yang
- Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital Beijing 100853, China
| | - Yong Song
- Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital Beijing 100853, China
| | - Wei Cai
- Department of Urology, Clinical Division of Surgery, Chinese PLA General Hospital Beijing 100853, China
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Cerbone L, Sternberg CN, Sengeløv L, Agerbaek M, Van Herpen C, Marreaud S, Collette S, Zhang J, Daugaard G. Results from a Phase I Study of Lapatinib with Gemcitabine and Cisplatin in Advanced or Metastatic Bladder Cancer: EORTC Trial 30061. Oncology 2015; 90:21-8. [PMID: 26468947 DOI: 10.1159/000440959] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2015] [Accepted: 09/07/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND/OBJECTIVE Lapatinib is a potent HER1 and HER2 inhibitor. Gemcitabine-cisplatin (GC) is a standard chemotherapy regimen for advanced/metastatic bladder cancer. This phase I study examined the safety of lapatinib in combination with GC in patients with bladder cancer. The primary aim was to determine the maximum tolerated dose (MTD) of lapatinib in combination with GC. METHODS A 3 + 3 dose escalation protocol was used with lapatinib at 750, 1,000 and then 1,250 mg. It was dosed daily with gemcitabine (1,000 mg/m2 on days 1, 8 and 15) and cisplatin (70 mg/m2 on day 2) every 28 days. In all, 18 patients with a median age of 63 years (range 50-77) were included; 3/6, 3/5 and 6/7 patients received lapatinib at 750, 1,000 and 1,250 mg, combined with GC, in cohorts 1, 2 and 3, respectively. RESULTS No dose-limiting toxicities (DLTs) were observed in cohort 1 or 2 (3 patients each); in cohort 3 (2 × 3 patients), 1 of the 6 patients presented DLTs (grade 4, treatment-related febrile neutropenia and renal failure). Twelve patients received 6 cycles. CONCLUSIONS Lapatinib at 750-1,250 mg combined with GC appears safe and tolerable. The MTD of lapatinib combined with GC in bladder cancer was 1,250 mg.
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Affiliation(s)
- Linda Cerbone
- Department of Medical Oncology, San Camillo and Forlanini Hospital, Rome, Italy
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Papadopoulos EI, Yousef GM, Scorilas A. Gemcitabine impacts differentially on bladder and kidney cancer cells: distinct modulations in the expression patterns of apoptosis-related microRNAs and BCL2 family genes. Tumour Biol 2015; 36:3197-207. [PMID: 25833690 DOI: 10.1007/s13277-014-2190-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2014] [Accepted: 06/03/2014] [Indexed: 12/22/2022] Open
Abstract
Bladder and renal cancer are two representative cases of tumors that respond differentially to gemcitabine. Previous studies have shown that gemcitabine can trigger apoptosis in various cancer cells. Herein, we sought to investigate the impact of gemcitabine on the expression levels of the BCL2 family members BCL2, BAX, and BCL2L12 and the apoptosis-related microRNAs miR-182, miR-96, miR-145, and miR-16 in the human bladder and kidney cancer cell lines T24 and Caki-1, respectively. Cancer cells' viability as well as the IC50 doses of gemcitabine were estimated by the MTT assay, while the detection of cleaved PARP via Western blotting was used as an indicator of apoptosis. Furthermore, T24 and Caki-1 cells' ability to recover from treatment was also monitored. Two different highly sensitive quantitative real-time RT-PCR methodologies were developed in order to assess the expression levels of BCL2 family genes and microRNAs. Exposure of cancer cells to gemcitabine produced the IC50 values of 30 and 3 nM for Caki-1 and T24 cells, correspondingly, while cleaved PARP was detected only in Caki-1 cells. T24 cells demonstrated the ability to recover from gemcitabine treatment, whereas Caki-1 cells' recovery capability was dependent on the initial time of exposure. BCL2 and BAX were significantly modulated in treated Caki-1 cells. Instead, T24 cells exhibited alterations only in the latter, as well as in all studied microRNAs. Therefore, according to our data, bladder and renal cancer cells' response to gemcitabine is accompanied by distinct alterations in the expression levels of their apoptosis-related genes and microRNAs.
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Affiliation(s)
- Emmanuel I Papadopoulos
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens, Panepistimiopolis, Athens, 15701, Greece
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Lobb I, Sonke E, Aboalsamh G, Sener A. Hydrogen sulphide and the kidney: Important roles in renal physiology and pathogenesis and treatment of kidney injury and disease. Nitric Oxide 2015; 46:55-65. [DOI: 10.1016/j.niox.2014.10.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 10/10/2014] [Accepted: 10/20/2014] [Indexed: 01/04/2023]
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Lucca I, Kassouf W, Kapoor A, Fairey A, Rendon RA, Izawa JI, Black PC, Fajkovic H, Seitz C, Remzi M, Nyirády P, Rouprêt M, Margulis V, Lotan Y, de Martino M, Hofbauer SL, Karakiewicz PI, Briganti A, Novara G, Shariat SF, Klatte T. The role of adjuvant chemotherapy for lymph node-positive upper tract urothelial carcinoma following radical nephroureterectomy: a retrospective study. BJU Int 2015; 116:72-8. [PMID: 24825476 DOI: 10.1111/bju.12801] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To evaluate the effect of adjuvant chemotherapy (AC) on mortality after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) with positive lymph nodes (LNs) and to identify patient subgroups that are most likely to benefit from AC. PATIENTS AND METHODS We retrospectively analysed data of 263 patients with LN-positive UTUC, who underwent full surgical resection. In all, 107 patients (41%) received three to six cycles of AC, while 156 (59.3%) were treated with RNU alone. UTUC-related mortality was evaluated using competing-risks regression models. RESULTS In all patients (T(all) N+), administration of AC had no significant impact on UTUC-related mortality on univariable (P = 0.49) and multivariable (P = 0.11) analysis. Further stratified analyses showed that only N+ patients with pT3-4 disease benefited from AC. In this subgroup, AC reduced UTUC-related mortality by 34% (P = 0.019). The absolute difference in mortality was 10% after the first year and increased to 23% after 5 years. On multivariable analysis, administration of AC was associated with significantly reduced UTUC-related mortality (subhazard ratio 0.67, P = 0.022). Limitations of this study are the retrospective non-randomised design, selection bias, absence of a central pathological review and different AC protocols. CONCLUSIONS AC seems to reduce mortality in patients with pT3-4 LN-positive UTUC after RNU. This subgroup of LN-positive patients could serve as target population for an AC prospective randomised trial.
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Affiliation(s)
- Ilaria Lucca
- Department of Urology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Wassim Kassouf
- Department of Urology, McGill University, Montreal, QC, Canada
| | - Anil Kapoor
- Department of Urology, McMaster University, Hamilton, ON, Canada
| | - Adrian Fairey
- Department of Surgery (Urology), University of Alberta, Edmonton, AB, Canada
| | | | - Jonathan I Izawa
- Department of Surgery (Urology), University of Western Ontario, London, ON, Canada
| | - Peter C Black
- Department of Urological Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Harun Fajkovic
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Christian Seitz
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Mesut Remzi
- Department of Urology, Landeskrankenhaus Weinviertel-Korneuburg, Korneuburg, Austria
| | - Peter Nyirády
- Department of Urology, Semmelweis University, Budapest, Hungary
| | - Morgan Rouprêt
- Department of Urology, Groupe Hospitalier Pitié - Salpêtrière, Assistance Publique Hopitaux de Paris, Faculty of Medicine Pierre et Marie Curie, Institut Universitaire de Cancérologie GRC5, University Paris 6, Paris, France
| | - Vitaly Margulis
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yair Lotan
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Michela de Martino
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Sebastian L Hofbauer
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
| | - Pierre I Karakiewicz
- Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Centre, Montreal, QC, Canada
| | - Alberto Briganti
- Department of Urology, Urological Research Institute, San Raffaele Scientific Institute, Milan, Italy
| | - Giacomo Novara
- Department of Surgical, Oncological and Gastroenterologic Sciences, Urology Clinic, University of Padua, Padua, Italy
| | - Shahrokh F Shariat
- Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX, USA.,Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA
| | - Tobias Klatte
- Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna General Hospital, Vienna, Austria
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Anabolic androgens affect the competitive interactions in cell migration and adhesion between normal mouse urothelial cells and urothelial carcinoma cells. Biochem Biophys Res Commun 2014; 452:322-7. [PMID: 25159849 DOI: 10.1016/j.bbrc.2014.08.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Accepted: 08/08/2014] [Indexed: 12/17/2022]
Abstract
The urothelium is constantly rebuilt by normal urothelial cells to regenerate damaged tissues caused by stimuli in urine. However, the urothelial carcinoma cells expand the territory by aberrant growth of tumor cells, which migrate and occupy the damaged tissues to spread outside and disrupt the normal cells and organized tissues and form a tumor. Therefore, the interaction between normal urothelial cells and urothelial carcinoma cells affect the initiation and progression of urothelial tumors if normal urothelial cells fail to migrate and adhere to the damages sites to regenerate the tissues. Here, comparing normal murine urothelial cells with murine urothelial carcinoma cells (MBT-2), we found that normal cells had less migration ability than carcinoma cells. And in our co-culture system we found that carcinoma cells had propensity migrating toward normal urothelial cells and carcinoma cells had more advantages to adhere than normal cells. To reverse this condition, we used anabolic androgen, dihyrotestosterone (DHT) to treat normal cells and found that DHT treatment increased the migration ability of normal urothelial cells toward carcinoma cells and the adhesion capacity in competition with carcinoma cells. This study provides the base of a novel therapeutic approach by using anabolic hormone-enforced normal urothelial cells to regenerate the damage urothelium and defend against the occupancy of carcinoma cells to thwart cancer development and recurrence.
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Pinto-Leite R, Arantes-Rodrigues R, Ferreira R, Palmeira C, Oliveira PA, Santos L. Treatment of muscle invasive urinary bladders tumors: A potential role of the mTOR inhibitors. ACTA ACUST UNITED AC 2014. [DOI: 10.1016/j.biomag.2014.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Down-regulation of miR-29c in human bladder cancer and the inhibition of proliferation in T24 cell via PI3K-AKT pathway. Med Oncol 2014; 31:65. [PMID: 24952510 DOI: 10.1007/s12032-014-0065-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2014] [Accepted: 06/02/2014] [Indexed: 10/25/2022]
Abstract
The purpose of this study was to explore new tumor suppressor microRNA in bladder cancer and to conduct functional analysis of its suppressive role. To investigate the expression of miR-29c, qRT-PCR was used in 30 pairs of bladder cancer tissues and normal tissues (adjacent bladder tissue samples). The expression of miR-29c was down regulated in bladder cancer tissues compared with normal tissues. Also, the low-level expression of miR-29c was associated with tumor stage (P = 0.002), and ectopic over-expression of miR-29c in T24 cells can significantly inhibit cell proliferation, decrease motility, suppress the G1/S cell cycle transition and induce apoptosis. Furthermore, it could cause a decrease in AKT and GSK-3β phosphorylation. While LY294002 reduced the protein level of pAKT, the over-expression of miR-29c can further decrease its level in T24 cells pretreated with LY294002. Our study also indicated that the proliferation inhibition of T24 may take place via AKT-GSK3β pathway. Thus, miR-29c could be an active player in disease state of bladder cancer and it may be a promising tumor suppressor in bladder cancer.
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Knapp DW, Ramos-Vara JA, Moore GE, Dhawan D, Bonney PL, Young KE. Urinary Bladder Cancer in Dogs, a Naturally Occurring Model for Cancer Biology and Drug Development. ILAR J 2014; 55:100-18. [DOI: 10.1093/ilar/ilu018] [Citation(s) in RCA: 150] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
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47
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Vinflunine for the treatment of metastatic transitional cell carcinoma: recent evidence from clinical trials and observational studies. ACTA ACUST UNITED AC 2014. [DOI: 10.4155/cli.14.15] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Oliveira PA, Arantes-Rodrigues R, Vasconcelos-Nóbrega C. Animal models of urinary bladder cancer and their application to novel drug discovery. Expert Opin Drug Discov 2014; 9:485-503. [DOI: 10.1517/17460441.2014.902930] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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49
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Pinto-Leite R, Carreira I, Melo J, Ferreira SI, Ribeiro I, Ferreira J, Filipe M, Bernardo C, Arantes-Rodrigues R, Oliveira P, Santos L. Genomic characterization of three urinary bladder cancer cell lines: understanding genomic types of urinary bladder cancer. Tumour Biol 2014; 35:4599-617. [PMID: 24459064 DOI: 10.1007/s13277-013-1604-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2013] [Accepted: 12/30/2013] [Indexed: 11/25/2022] Open
Abstract
Several genomic regions are frequently altered and associated with the type, stage and progression of urinary bladder cancer (UBC). We present the characterization of 5637, T24 and HT1376 UBC cell lines by karyotyping, fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis. Some cytogenetic anomalies present in UBC were found in the three cell lines, such as chromosome 20 aneuploidy and the loss of 9p21. Some gene loci losses (e.g. CDKN2A) and gains (e.g. HRAS, BCL2L1 and PTPN1) were coincident across all cell lines. Although some significant heterogeneity and complexity were detected between them, their genomic profiles exhibited a similar pattern to UBC. We suggest that 5637 and HT1376 represent the E2F3/RB1 pathway due to amplification of 6p22.3, concomitant with loss of one copy of RB1 and mutation of the remaining copy. The HT1376 presented a 10q deletion involving PTEN region and no alteration of PIK3CA region which, in combination with the inactivation of TP53, bears more invasive and metastatic properties than 5637. The T24 belongs to the alternative pathway of FGFR3/CCND1 by presenting mutated HRAS and over-represented CCND1. These cell lines cover the more frequent subtypes of UBC and are reliable models that can be used, as a group, in preclinical studies.
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Affiliation(s)
- Rosário Pinto-Leite
- Cytogenetic Laboratory, Department of Human Genetics, Hospital Center of Trás-os-Montes and Alto Douro, Vila Real, Portugal
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Gerhardt D, Bertola G, Dietrich F, Figueiró F, Zanotto-Filho A, Moreira Fonseca JC, Morrone FB, Barrios CH, Battastini AMO, Salbego CG. Boldine induces cell cycle arrest and apoptosis in T24 human bladder cancer cell line via regulation of ERK, AKT, and GSK-3β. Urol Oncol 2014; 32:36.e1-9. [DOI: 10.1016/j.urolonc.2013.02.012] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2012] [Revised: 04/11/2012] [Accepted: 04/13/2012] [Indexed: 11/16/2022]
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