Exp Mol Med.
2004 Oct;36(5):411-419.
Enhancement of radiosensitivity by combined ceramide and dimethylsphingosine treatment in lung cancer cells
- Affiliations
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- 1Laboratory of Immunology, Korea Institute of Radiological and Medical Sciences, KAERI 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Korea. immu@kcch.re.kr
- 2Laboratory of Biopharmaceutical Processes, Graduate School of Life Sciences and Biotechnology, Korea University, Anam-dong, Sungbuk-gu, Seoul 136-701, Korea.
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.
Keyword
MeSH Terms
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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
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