Treatment of cells with cisplatin induces a sustained activation of the stress activated protein kinase SAPK/JNK and the mitogen-activated protein kinase p38. Activation of JNK by cisplatin is necessary for the induction of apoptosis. Expression of the MAPK phosphatases CL100/MKP-1 and hVH-5 selectively prevents JNK/SAPK activation by cisplatin in a dose dependent fashion and results in protection against cisplatin-induced apoptosis. In contrast, expression of the ERK-specific phosphatase Pyst1 inhibits JNK/SAPK activity only when expressed at very high levels and does not confer protection against cisplatin. Furthermore, expression of a catalytically inactive mutant of CL100 in 293 cells decreases the IC50 for cisplatin and increases the toxicity of transplatin. This effect seems to be mediated by an increase in JNK activity since p38 activity is unaffected. These results suggest that dual-specificity MAPK phosphatases may be candidate drug targets in order to optimize cisplatin based therapeutic protocols.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/sj.onc.1203887 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Serum cardiac and inflammatory biomarker levels following chemotherapy among female patients with breast cancer attending at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia.
BMC Cancer
January 2025
Department of Biomedical Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, P.O. Box 79, Ethiopia.
Background: Chemotherapy is a well-established therapeutic approach for several malignancies, including breast cancer (BCa). However, the clinical efficacy of this drug is limited by cardiotoxicity. Assessing multiple cardiac biomarkers can help identify patients at risk of adverse outcomes from chemotherapy.
View Article and Find Full Text PDFConcurrent inhibition of p300/CBP and FLT3 enhances cytotoxicity and overcomes resistance in acute myeloid leukemia.
Acta Pharmacol Sin
January 2025
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
FMS-like tyrosine kinase-3 (FLT3), a class 3 receptor tyrosine kinase, can be activated by mutations of internal tandem duplication (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3-TKD), leading to constitutive activation of downstream signaling cascades, including the JAK/STAT5, PI3K/AKT/mTOR and RAS/MAPK pathways, which promote the progression of leukemic cells. Despite the initial promise of FLT3 inhibitors, the discouraging outcomes in the treatment of FLT3-ITD-positive acute myeloid leukemia (AML) promote the pursuit of more potent and enduring therapeutic approaches. The histone acetyltransferase complex comprising the E1A binding protein P300 and its paralog CREB-binding protein (p300/CBP) is a promising therapeutic target, but the development of effective p300/CBP inhibitors faces challenges due to inherent resistance and low efficacy, often exacerbated by the absence of reliable clinical biomarkers for patient stratification.
View Article and Find Full Text PDFAn mTOR inhibitor discovery system using drug-sensitized yeast.
Geroscience
January 2025
Department of Biomedical Sciences, Western University of Health Sciences, Lebanon, OR, 97355, USA.
Inhibition of the target of rapamycin (TOR/mTOR) protein kinase by the drug rapamycin extends lifespan and health span across diverse species. However, rapamycin has potential off-target and side effects that warrant the discovery of additional TOR inhibitors. TOR was initially discovered in Saccharomyces cerevisiae (yeast) which contains two TOR paralogs, TOR1 and TOR2.
View Article and Find Full Text PDFProspective Investigation Unravels Plasma Proteomic Links to Dementia.
Mol Neurobiol
January 2025
Research and Innovation Center, Shanghai Pudong Hospital, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University, Shanghai, 200433, China.
Investigating plasma proteomic signatures of dementia offers insights into its pathology, aids biomarker discovery, supports disease monitoring, and informs drug development. Here, we analyzed data from 48,367 UK Biobank participants with proteomic profiling. Using Cox and generalized linear models, we examined the longitudinal associations between proteomic signatures and dementia-related phenotypes.
View Article and Find Full Text PDFDNA-Dependent Protein Kinase Inhibitor Peposertib Enhances Efficacy of Lu-Based Radioimmunotherapy in Preclinical Models of Prostate and Renal Cell Carcinoma.
J Nucl Med
January 2025
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia;
Novel radiation sensitizers, including inhibitors targeting DNA damage response, have been developed to enhance the efficacy of anticancer treatments that induce DNA damage in cancer cells. Peposertib, a potent, selective, and orally administered inhibitor of DNA-dependent protein kinase, impedes the nonhomologous end-joining mechanism for DNA double-strand break (DSB) repair. We investigated radioimmunotherapy alone or with peposertib in preclinical models of renal cell carcinoma (RCC) or prostate cancer.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!