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October 1, 2016: Cancer Research
Junjie Xu, Hui Lin, Gonghui Li, Yin Sun, Liang Shi, Wen-Lung Ma, Jiang Chen, Xiujun Cai, Chawnshang Chang
Sorafenib is currently used as a standard treatment to suppress the progression of hepatocellular carcinoma (HCC), especially in advanced stages. However, patients who receive Sorafenib treatment eventually develop resistance without clear mechanisms. It's badly in need of better efficacy of Sorafenib treatment in combination with other therapies. Here we demonstrated that the treatment combining Sorafenib with ASC-J9(®) could synergistically suppress HCC progression via altering cell-cycle regulation, apoptosis and invasion...
September 26, 2016: International Journal of Cancer. Journal International du Cancer
Cassandra Chong, Yiwei Wang, Peter K M Maitz, Ulla Simanainen, Zhe Li
Current dermal regenerative scafolds provide wound coverage, and structural support and guidance for tissue repair, but usually lack enough bio-signals needed for speeding up skin cell growth, migration, wound closure, and skin regeneration. In this study, an androgen receptor (AR) inhibitor called ASC-J9 is used to demonstrate the concept and feasibility of fabricating drug-loaded scafolds via electrospinning. Inhibition of androgen is known to promote skin wound healing. The novel ASC-J9 - loaded porous scafold was fabricated for skin wound repair using electrospun fibers of collagen and polycaprolactone (PCL) blend...
2013: Burns and trauma
Shin-Jen Lin, Fu-Ju Chou, Chang-Yi Lin, Hong-Chiang Chang, Shuyuan Yeh, Chawnshang Chang
Prostatitis is a common disease contributing to 8% of all urologist visits. Yet the etiology and effective treatment remain to be further elucidated. Using a non-obese diabetes mouse model that can be induced by autoimmune response for the spontaneous development of prostatitis, we found that injection of the ASC-J9® at 75 mg/Kg body weight/48 hours led to significantly suppressed prostatitis that was accompanied with reduction of lymphocyte infiltration with reduced CD4+ T cells in prostate. In vitro studies with a co-culture system also confirmed that ASC-J9® treatment could suppress the CD4+ T cell migration to prostate stromal cells...
August 22, 2016: Oncotarget
Ronghao Wang, Wanying Lin, Changyi Lin, Lei Li, Yin Sun, Chawnshang Chang
Androgen deprivation therapy (ADT) with the newly developed powerful anti-androgen enzalutamide (Enz, also known as MDV3100) has promising therapeutic effects to suppress castration resistant prostate cancer (CRPC) and extending patients' lives an extra 4.8 months. However, most Enz therapy eventually fails with the development of Enz resistance. The detailed mechanisms how CRPC develops Enz resistance remain unclear and may involve multiple mechanisms. Among them, the induction of the androgen receptor (AR) mutant AR-F876L in some CRPC patients may represent one driving force that confers Enz resistance...
August 28, 2016: Cancer Letters
Simeng Wen, Jing Tian, Yuanjie Niu, Lei Li, Shuyuan Yeh, Chawnshang Chang
Early studies suggested that prostate cancer (PCa) stem/progenitor (S/P) cells might play key roles to promote the tumor initiation and metastasis. Yet their linkage to the failure of androgen deprivation therapy (ADT), however, remains unclear. Here we demonstrated that the ADT with anti-androgens Casodex (also known as Bicalutamide) and Enzalutamide (also known as MDV3100), but not the newly identified AR degradation enhancer, ASC-J9(®), increased PCa S/P population, which might then lead to enhance the PCa cell invasion...
July 1, 2016: Cancer Letters
Simeng Wen, Yuanjie Niu, Soo Ok Lee, Shuyuan Yeh, Zhiqun Shang, Hengheng Gao, Yanjun Li, Fuju Chou, Chawnshang Chang
Fatty acid synthase (FASN) is the key enzyme for the control of fatty acid synthesis that contributes significantly to the prostate cancer (PCa) progression. It was reported that androgens were able to induce FASN expression in PCa, and addition of the anti-androgen Casodex might suppress the androgen-induced FASN expression. However, here we found androgen-deprivation-therapy (ADT) with anti-androgens Bicalutamide (Casodex) or Enzalutamide (MDV3100) had little effect to suppress FASN expression and FASN-mediated cell growth and invasion during the castration resistant stage when the androgen concentration is 1 nM DHT (dihydrotestosterone)...
February 19, 2016: Molecular Carcinogenesis
Chiung-Kuei Huang, Jie Luo, Kuo-Pao Lai, Ronghao Wang, Haiyan Pang, Eugene Chang, Chen Yan, Janet Sparks, Soo Ok Lee, Joshua Cho, Chawnshang Chang
Sex difference is a risk factor for abdominal aortic aneurysm (AAA) formation yet the reason for male predominance remains unclear. Androgen and the androgen receptor (AR) influence the male sex difference, indicating that AR signaling may affect AAA development. Using angiotensin II–induced AAA in apolipoprotein E null mouse models (82.4% AAA incidence), we found that mice lacking AR failed to develop AAA and aorta had dramatically reduced macrophages infiltration and intact elastic fibers. These findings suggested that AR expression in endothelial cells, macrophages, or smooth muscle cells might play a role in AAA development...
October 2015: Hypertension
Zhiqun Shang, Yanjun Li, Minghao Zhang, Jing Tian, Ruifa Han, Chih-Rong Shyr, Edward Messing, Shuyuan Yeh, Yuanjie Niu, Chawnshang Chang
Recent studies suggest that the androgen receptor (AR) might play important roles in influencing bladder cancer progression, yet its clinical application remains unclear. Here, we developed a new combined therapy with Bacillus Calmette-Guérin (BCG) and the AR degradation enhancer ASC-J9 or antiandrogen hydroxyflutamide (HF) to better suppress bladder cancer progression. Mechanism dissection revealed that ASC-J9 treatment enhanced BCG efficacy to suppress bladder cancer cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the bladder cancer cells through increased integrin-α5β1 expression and IL6 release...
November 2015: Molecular Cancer Therapeutics
Shinichi Yamashita, Yoichi Arai
Androgen deprivation therapy has been the standard treatment for the patients with advanced prostate cancer. Androgen deprivation therapy initially suppresses the growth of prostate cancer. However, most patients eventually progress to castration-resistant prostate cancer. Novel drugs, including enzalutamide and abiraterone acetate, are recently able to be used for the patients with castration-resistant prostate cancer. Even so, the therapeutic options for castration-resistant prostate cancer are not enough...
December 2014: Nihon Rinsho. Japanese Journal of Clinical Medicine
Simeng Wen, Hong-Chiang Chang, Jing Tian, Zhiqun Shang, Yuanjie Niu, Chawnshang Chang
The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles...
February 2015: American Journal of Pathology
Liang Liang, Lei Li, Jing Tian, Soo Ok Lee, Qiang Dang, Chiung-Kuei Huang, Shuyuan Yeh, Erdal Erturk, David Bushinsky, Luke S Chang, Dalin He, Chawnshang Chang
Males develop kidney stones far more frequently than females with a ratio of 2-3:1, suggesting that androgen receptor (AR) signaling might play a key role in the development of nephrolithiasis. Using the cre-loxP system to selectively knock out AR in glyoxylate-induced calcium oxalate (CaOx) crystal mouse models, we found that the mice lacking hepatic AR had less oxalate biosynthesis, which might lead to lower CaOx crystal formation, and that the mice lacking kidney proximal or distal epithelial AR also had lower CaOx crystal formation...
August 2014: Molecular Endocrinology
Paolo Verderio, Laura Pandolfi, Serena Mazzucchelli, Maria Rosaria Marinozzi, Renzo Vanna, Furio Gramatica, Fabio Corsi, Miriam Colombo, Carlo Morasso, Davide Prosperi
Among polymeric nanoparticles designed for cancer therapy, PLGA nanoparticles have become one of the most popular polymeric devices for chemotherapeutic-based nanoformulations against several kinds of malignant diseases. Promising properties, including long-circulation time, enhanced tumor localization, interference with "multidrug" resistance effects, and environmental biodegradability, often result in an improvement of the drug bioavailability and effectiveness. In the present work, we have synthesized 1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one (ASC-J9) and developed uniform ASC-J9-loaded PLGA nanoparticles of about 120 nm, which have been prepared by a single-emulsion process...
August 4, 2014: Molecular Pharmaceutics
Dalin He, Lei Li, Guodong Zhu, Liang Liang, Zhenfeng Guan, Luke Chang, Yuan Chen, Shuyuan Yeh, Chawnshang Chang
Males have a higher incidence of renal cell carcinoma (RCC) than females, but the reason for this gender difference is unknown. Addressing this question, we report the discovery of an androgen receptor (AR)-induced HIF2α/VEGF signal that drives RCC progression. AR attenuation or augmentation in RCC cells altered their proliferation, migration, and invasion in multiple models in vitro and in vivo. Mechanistic investigations revealed that AR targeting inhibited RCC cell migration and invasion by modulating HIF2α/VEGF signals at the level of mRNA and protein expression...
August 15, 2014: Cancer Research
Chiung-Kuei Huang, Haiyan Pang, Lin Wang, Yuanjie Niu, Jie Luo, Eugene Chang, Janet D Sparks, Soo Ok Lee, Chawnshang Chang
The male sex has a higher risk to develop coronary artery diseases, including atherosclerosis. The androgen receptor (AR) is expressed in several atherosclerosis-associated cell types, including monocytes/macrophages, endothelial cells (ECs), and smooth muscle cells (SMCs), but its pathophysiological role in each cell type during the development of atherosclerotic lesions remains unclear. Using the Cre-loxP system, we selectively knocked out AR in these 3 cell types and the resultant AR knockout (ARKO) mice, monocyte/macrophage ARKO, EC-ARKO, and SMC-ARKO, were then crossed with the low-density lipoprotein receptor (LDLR) deficient (LDLR(-/-)) mice to develop monocyte/macrophage ARKO-LDLR(-/-), EC-ARKO-LDLR(-/-), and SMC-ARKO-LDLR(-/-) mice for the study of atherosclerosis...
June 2014: Hypertension
Kouji Izumi, Chawnshang Chang
Inflammatory cytokines and chemokines released by macrophages in the prostate cancer microenvironment may signal via the androgen receptor (AR) to influence tumor progression. In particular, macrophages appear to promote tumorigenesis by altering the chemokine (C-C motif) ligand 4 (CCL4)/AR signaling axis. This process can be blocked by ASC-J9(®), an enhancer of AR degradation. ASC-J9(®) also inhibits the CCL2-dependent, signal transducer and activator of transcription 3 (STAT3)-mediated pro-metastatic signaling cascade that is generally activated by androgen deprivation therapy...
December 1, 2013: Oncoimmunology
Shu Fang Soh, Chiung-Kuei Huang, Soo Ok Lee, Defeng Xu, Shuyuan Yeh, Jun Li, Eu Leong Yong, Yinhan Gong, Chawnshang Chang
A novel androgen receptor (AR) degradation enhancer ASC-J9(®) has displayed beneficial effects during the in vitro and in vivo studies for treatment of prostate cancer, liver cancer, bladder cancer and spinal and bulbar muscular atrophy (SBMA). It works mainly via the degradation of AR with minimal side effects on the tested mice. Here we developed a fast, robust and more sensitive method for the quantification of ASC-J9(®) in 100μL of mouse serum by using liquid chromatography tandem mass spectrometry (LC-MS/MS)...
January 2014: Journal of Pharmaceutical and Biomedical Analysis
T-H Lin, K Izumi, S O Lee, W-J Lin, S Yeh, C Chang
Despite androgen deprivation therapy (ADT) suppression of prostate cancer (PCa) growth, its overall effects on PCa metastasis remain unclear. Using human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells-macrophages co-culture systems, we found currently used anti-androgens, MDV3100 (enzalutamide) or Casodex (bicalutamide), promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion. In contrast, the AR degradation enhancer, ASC-J9, suppressed both macrophage migration and subsequent PCa cell invasion...
2013: Cell Death & Disease
Kuo-Pao Lai, Chiung-Kuei Huang, Lei-Ya Fang, Kouji Izumi, Chi-Wen Lo, Ronald Wood, Jon Kindblom, Shuyuan Yeh, Chawnshang Chang
Stromal-epithelial interaction plays a pivotal role to mediate the normal prostate growth, the pathogenesis of benign prostatic hyperplasia (BPH), and prostate cancer development. Until now, the stromal androgen receptor (AR) functions in the BPH development, and the underlying mechanisms remain largely unknown. Here we used a genetic knockout approach to ablate stromal fibromuscular (fibroblasts and smooth muscle cells) AR in a probasin promoter-driven prolactin transgenic mouse model (Pb-PRL tg mice) that could spontaneously develop prostate hyperplasia to partially mimic human BPH development...
October 2013: Molecular Endocrinology
Lei-Ya Fang, Kouji Izumi, Kuo-Pao Lai, Liang Liang, Lei Li, Hiroshi Miyamoto, Wen-Jye Lin, Chawnshang Chang
Infiltrating macrophages are a key component of inflammation during tumorigenesis, but the direct evidence of such linkage remains unclear. We report here that persistent coculturing of immortalized prostate epithelial cells with macrophages, without adding any carcinogens, induces prostate tumorigenesis and that induction involves the alteration of signaling of macrophage androgen receptor (AR)-inflammatory chemokine CCL4-STAT3 activation as well as epithelial-to-mesenchymal transition and downregulation of p53/PTEN tumor suppressors...
September 15, 2013: Cancer Research
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