Aberrant signal transduction has been implicated in malignant transformation, growth, and progression. This has led to the proposal to use inhibitors of signal transduction pathways to treat cancer. One approach to circumventing potential toxicity and improving efficacy would be to target pathways upon which cancer cells selectively depend. Pathways associated with the malignant process involve calcium fluxes, the release of arachidonic acid, and the generation of phosphoinositides. In this report, CAI (L651582, NSC 609974), a substituted carboxyamido-imidazole and novel inhibitor of these selected signal transduction pathways, inhibits anchorage-dependent and -independent growth in a large series of human cancer cell lines. CAI pretreatment of HT-29 human colon cancer and 5R ras-transfected rat embryo fibroblast cells inhibits the formation and growth of experimental pulmonary metastases in nude mice. Oral administration of CAI in PEG-400 vehicle arrests growth and metastasis of transplanted human melanoma and ovarian cancer xenografts. No significant gross or histological toxicity was observed at CAI doses yielding blood levels in the concentration range demonstrated to inhibit select signal transduction pathways in vitro. These data indicate the feasibility and demonstrate a potential selectivity and sensitivity of using specific signal transduction inhibitors for the experimental treatment of cancer.
Download full-text PDF |
Source |
|---|
Publication Analysis
Top Keywords
Similar Publications
CBX2 suppresses interferon signaling to diminish tumor immunogenicity via a noncanonical corepressor complex.
Proc Natl Acad Sci U S A
February 2025
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510050, China.
Chromobox 2 (CBX2), a crucial component of the polycomb repressive complex (PRC), has been implicated in the development of various human cancers. However, its role in the regulation of tumor immunogenicity and immune evasion remains inadequately understood. In this study, we found that ablation of CBX2 led to tumor growth inhibition, activation of the tumor immune microenvironment, and enhanced therapeutic efficacy of anti-PD1 or adoptive T cell therapies by using murine syngeneic tumor models.
View Article and Find Full Text PDFActivation of the conserved Hippo kinases by inflammasome-triggered proteolytic cleavage controls programmed cell death in macrophages.
Proc Natl Acad Sci U S A
February 2025
Department of Biological Sciences, College of Liberal Arts and Sciences, Wayne State University, Detroit, MI 48202.
The mammalian Hippo kinases, MST1 and MST2, regulate organ development and suppress tumor formation by balancing cell proliferation and death. In macrophages, inflammasomes detect molecular patterns from invading pathogens or damaged host cells and trigger programmed cell death. In addition to lytic pyroptosis, the signatures associated with apoptosis are induced by inflammasome activation, but how the inflammasomes coordinate different cell death processes remains unclear.
View Article and Find Full Text PDFTIR signaling activates caspase-like immunity in bacteria.
Science
January 2025
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity and regulated cell death in humans. We describe a bacterial immune system comprising both a caspase-like protease and a TIR-domain protein. We found that the TIR protein, once it recognizes phage invasion, produces the previously unknown immune signaling molecule adenosine 5'-diphosphate-cyclo[N7:1'']-ribose (N7-cADPR).
View Article and Find Full Text PDFIL-34 aggravates myocardial ischemia-reperfusion injury by upregulating the HMGB1-IL-17A-IL-6 axis through the JAK signaling pathway.
PLoS One
January 2025
Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, PR China.
Interleukin-34 (IL-34) was recently reported to be a new biomarker for atherosclerosis diseases, such as coronary artery disease and vascular dementia. IL-34 regulates the expression of proinflammatory cytokines (IL-17A, IL-1 and IL-6), which are classical cytokines involved in myocardial ischemia‒reperfusion (MI/R) injury. However, the exact role of IL-34 in MI/R remains unknown.
View Article and Find Full Text PDFGuards and decoys: RIPoptosome and inflammasome pathway regulators of bacterial effector-triggered immunity.
PLoS Pathog
January 2025
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
Virulent microbes produce proteins that interact with host cell targets to promote pathogenesis. For example, virulent bacterial pathogens have proteins called effectors that are typically enzymes and are secreted into host cells. To detect and respond to the activities of effectors, diverse phyla of host organisms evolved effector-triggered immunity (ETI).
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!