Ceramide involvement in homocamptothecin- and camptothecin-induced cytotoxicity and apoptosis in colon HT29 cells.
Topoisomerase I inhibitors of the camptothecin (CPT) family have emerged as potent clinical chemotherapeutic agents in first-line treatment of solid colorectal cancer and in second-line for 5-fluorouracil resistant patients. CPT and homocamptothecin (hCPT), derivative with enhanced lactone stability, induced growth inhibition in HT29 cells via p53-independent apoptosis. hCPT- and CPT-induced apoptosis was dependent on caspase-3 but not caspase-1. We report here substantial evidence that ceramide, resulting from de novo pathway or catabolism modulation, acted as a second messenger of these antitumor drugs in HT29 cells and leads to the activation of caspase-3. In addition, hCPT and CPT may favor ceramide signaling by disturbing sites of synthesis (Golgi) and trafficking of glucosylceramide from Golgi to lipid droplets. This work contributes to the understanding of the mechanism of action of CPTs, and suggests that inhibitors of glycosylation or activators of de novo metabolism could be of clinical interest in enhancing the effects of CPTs.
Chauvier
David
D
Unité MéDIAN, CNRS FRE2141, IFR53, Faculté de Pharmacie, 51096 Reims, France.
Morjani
Hamid
H
Manfait
Michel
M
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016158:Genes, p53; D019073:HT29 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000737:chemistry; D009154:Mutation; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors; D013109:Sphingomyelins / Q000378:metabolism; D021601:trans-Golgi Network / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D002518:Ceramides; D004791:Enzyme Inhibitors; D008055:Lipids; C105705:N-(5-(5,7-dimethyl Bodipy)-1-pentanoyl)-erythro-sphingosylphosphorylcholine; D013109:Sphingomyelins; C120029:homocamptothecin; D013108:Sphingomyelin Phosphodiesterase; D020169:Caspases; D002166:Camptothecin