Enhancement of radiosensitivity by combined ceramide and dimethylsphingosine treatment in lung cancer cells.
- Author:
Hye Won PARK
1
;
Jie Young SONG
;
Ki Sung KIM
;
Youngsoo HAN
;
Chan Wha KIM
;
Seh Yoon YI
;
Yeon Sook YUN
Author Information
1. Laboratory of Immunology, Korea Institute of Radiological and Medical Sciences, KAERI 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Korea. immu@kcch.re.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
apoptosis;
ceramide;
DMS;
radiosensitivity
- MeSH:
Animals;
Apoptosis/drug effects;
Carcinoma, Lewis Lung/metabolism/*radiotherapy;
Caspases/metabolism;
Cell Line, Tumor;
Cell Survival/drug effects/radiation effects;
Gene Expression;
Lung Neoplasms/metabolism/*radiotherapy;
Mice;
Proto-Oncogene Proteins/genetics/metabolism;
Proto-Oncogene Proteins c-bcl-2/genetics/metabolism;
Radiation Tolerance;
*Radiation-Sensitizing Agents;
Research Support, Non-U.S. Gov't;
Sphingosine/*analogs & derivatives/pharmacology/*therapeutic use
- From:Experimental & Molecular Medicine
2004;36(5):411-419
- CountryRepublic of Korea
- Language:English
-
Abstract:
Ceramide generated from sphingomyelin in response to ionizing radiation has been implicated as a second messenger to induce cellular proapoptotic signals. Both ceramide and its metabolic inhibitor, N, N-dimethyl-D-erythro-sphingosine (DMS), might lead to sustained ceramide accumulation in cells more efficiently, thereby sensitizing them to gamma-radiation-induced cell death. To delineate this problem, the clonogenic survival of Lewis lung carcinoma (LLC) cells was evaluated following exposure to radiation together with or without C2-ceramide, DMS, or both. The treatment of ceramide/DMS synergistically decreased the survival of the irradiated cells compared with treatment with ceramide or DMS alone. Ceramide/DMS-treated cells displayed several apoptotic features after gamma-irradiation, including increased sub G1 population, TUNEL-positive fraction, and poly-(ADP-ribose) polymerase (PARP) cleavage. We also observed ceramide/ DMS induced disruption of mitochondrial membrane potential (MMP) and activation of caspase- 9 and -3 in a radiation-dose-dependent manner. Furthermore, pretreatment of LLC cells with ceramide/DMS not only increased the protein expression level of Bax, but also decreased Bcl-2 after gamma-irradiation. Taken together, the present study indicates that the radiosensitizing activity of ceramide/DMS on LLC cells most likely reflects the dominance of pro-apoptotic signals related to the mitochondria-dependent pathway.
