Withaferin A (WA), a naturally occurring steroidal lactone, directly binds to Hsp90 and leads to the degradation of Hsp90 client protein. The purpose of this study is to investigate the structure activity relationship (SAR) of withanolides for their inhibition of Hsp90 and anti-proliferative activities in pancreatic cancer cells. In pancreatic cancer Panc-1 cells, withaferin A (WA) and its four analogues withanolide E (WE), 4-hydroxywithanolide E (HWE), 3-aziridinylwithaferin A (AzWA) inhibited cell proliferation with IC50 ranged from 1.0 to 2.8 μM. WA, WE, HWE, and AzWA also induced caspase-3 activity by 21-, 6-, 11- and 15-fold, respectively, in Panc-1 cells, while withaperuvin (WP) did not show any activity. Our data showed that WA, WE, HWE, and AzWA, but not WP, all directly bound to Hsp90 and induced Hsp90 aggregation,hence inhibited Hsp90 chaperone activity to induce degradation of Hsp90 client proteins Akt and Cdk4 through proteasome-dependent pathway in pancreatic cancer cells. However, only WA, HWE and AzWA disrupted Hsp90-Cdc37 complexes but not WE and WP. SAR study suggested that the C-5(6)-epoxy functional group contributes considerably for withanolide to bind to Hsp90, inhibit Hsp90 chaperone activity, and result in Hsp90 client protein depletion. Meanwhile, the hydroxyl group at C-4 of ring A may enhance withanolide to inhibit Hsp90 activity and disrupt Hsp90-Cdc37 interaction. These SAR data provide possible mechanisms of anti-proliferative action of withanolides.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865103 | PMC |
http://dx.doi.org/10.1007/s10637-013-9987-y | DOI Listing |
Front Immunol
January 2025
Department of Hepatobiliary Surgery, The Second Affiliated Hospital, Kunming Medical University, Kunming, China.
Purpose: This study aimed to investigate whether tumor-associated lymphatic vessel density (LVD) could predict the survival of patients with hepato-biliary-pancreatic (HBP) cancers after radical resection.
Methods: A systematic search was conducted using PubMed, Embase, and Cochrane Library from the inception to July 31, 2024 for literature that reported the role of LVD in overall survival (OS) and recurrence-free survival (RFS) of patients with HBP cancers after radical resection.
Results: Ten studies with 761 patients were included for the meta-analysis.
Front Oncol
January 2025
Research Institute, Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Goyang, Republic of Korea.
Background: Oncologic outcomes of conversion surgery for advanced pancreatic cancer (PC) have scarcely been reported. Therefore, this study aimed to investigate the outcomes of conversion surgery with preoperative treatment of FOLFIRINOX or gemcitabine with nab-paclitaxel (GnP) for patients with advanced PC including locally advanced or metastatic PC.
Methods: Using the National Health Insurance database between 2005 and 2020, we identified patients who underwent conversion surgery after chemotherapy with FOLFIRINOX or GnP for advanced PC.
Front Oncol
January 2025
Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Erythropoietin-producing hepatocellular (Eph) receptors comprise the largest group of surface receptors and are responsible for cellular signals. Eph/ephrin signaling has been identified to play a role in key cancer development and progression processes, especially in the upper gastrointestinal tract. The Eph/ephrin system has been described as a tumor suppressor in duodenal cancer, while in esophageal, gastric, hepatic, and pancreatic cancer, the system has been related to tumor progression.
View Article and Find Full Text PDFOncol Lett
March 2025
Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China.
The relationship between diabetes and pancreatic cancer is well documented; however, the effect of preoperative blood glucose levels on prognosis and postoperative complications is currently unclear. The present study aimed to investigate the effect of preoperative blood glucose levels on overall survival (OS) and postoperative complications in patients with pancreatic cancer. This retrospective study included 225 patients with pancreatic cancer treated at The Fourth Hospital of Hebei Medical University from January 2015 to December 2020.
View Article and Find Full Text PDFFront Endocrinol (Lausanne)
January 2025
School of Medicine, The South China University of Technology, Guangzhou, Guangdong, China.
Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis with a short median overall survival of 6-12 months and a low 5-year survival rate of approximately 3%. It is crucial to remove PanIN lesions to prevent the development of invasive PDAC, as PDAC spreads rapidly outside the pancreas. This review aims to provide the latest knowledge on PanIN risk, pathology, cellular origin, genetic susceptibility, and diagnosis, while identifying research gaps that require further investigation in this understudied area of precancerous lesions.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!