Low daunomycin concentrations protect colorectal cancer cells from hypoxia-induced apoptosis.
Hypoxia, a common feature of solid tumors, is a direct stress that triggers apoptosis in many cell types. Poor or irregular tumor vascularization also leads to a decreased drug diffusion and cancer cells distant from blood vessels (hypoxic cells) are exposed to low drug concentrations. In this report, we show that low daunomycin concentrations protect HCT116 colorectal cancer cells from hypoxia-induced apoptosis. While hypoxia induced p53 accumulation without expression of its responsive genes (bax and p21), daunomycin treatment restored p53 transactivation activity and cell cycle progression. We also demonstrated a role for Akt activation in daunomycin-induced protection through phosphorylation and inactivation of the Bcl-2 family proapoptotic factor Bad. Our data therefore suggest that chemotherapy could possibly, because of low concentrations in poorly vascularized tumors, protect cancer cells from hypoxia-induced cytotoxicity.
Lechanteur
Chantal
C
Laboratory of Medical Chemistry and Human Genetics, Center for Biomedical Integrated Genoproteomics, University of Liège, Belgium.
Jacobs
Nathalie
N
Greimers
Roland
R
Benoît
Valérie
V
Deregowski
Valérie
V
Chariot
Alain
A
Merville
Marie-Paule
MP
Bours
Vincent
V
D017209:Apoptosis / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000502:physiology; D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019610:Cytoprotection; D003630:Daunorubicin / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003630:Daunorubicin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53; C493956:CDKN1A protein, human; C494918:AKT1 protein, human