Understanding interactions between and among apoptosis inducing pathways in tumor cells.
It has become increasingly clear that the induction of apoptosis in tumor cells can occur by at least three different pathways involving the cell surface receptors, the mitochondria and the endoplasmic reticulum. Specific drugs and conditions can trigger the apoptotic response via one of the three known pathways. What is less clear is how these three pathways can interact synergistically or antagonistically to influence a common convergence step leading to the programmed cell death. In this report we present data to show that fenretinide (a synthetic retinoid) potentiates the apoptotic effects of parthenolide (a drug that inhibits the activation of NF-kappa B) and BAY 11-7085 (an inhibitor of I-kappa B-alpha kinase). This potentiation of apoptosis by fenretinide is seen in the p53-deficient, deoxyadenosine-resistant L1210 cells, but not in the parental L1210 cells that express a mutant p53. These effects are seen at a concentration of fenretinide that have little effect by itself. These data strongly suggest that fenretinide activates or inhibits some step or pathway that interacts with the inhibition of NF-kappa B activation required for the apoptotic response. Since parthenolide, BAY 11-7085 and fenretinide are well known drugs in clinical trials, an understanding of the nature of the interactions between or among the apoptotic pathways could lead to the design of better clinical protocols using these drugs that will promote apoptosis in tumor cells.
Cory
Ann H
AH
Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Cory
Joseph G
JG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D003839:Deoxyadenosines / Q000494:pharmacology; D017313:Fenretinide / Q000494:pharmacology; D007939:Leukemia L1210 / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009336:Necrosis; D009369:Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D009570:Nitriles / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology*
C416282:BAY 11-7085; D003839:Deoxyadenosines; D016328:NF-kappa B; D009570:Nitriles; D012717:Sesquiterpenes; D013450:Sulfones; D017313:Fenretinide; C002669:parthenolide