Effect of artesunate on immune cells in ret-transgenic mouse melanoma model.
The antimalarial artesunate also exerts profound cytotoxicity toward tumor cells. Earlier investigations controversially discussed a possible immunosuppressive function of artemsinin and its derivatives. This poses the question, whether immunosuppressive activity counteracts the anticancer activity in vivo. To clarify this issue, we used a transgenic mouse spontaneous melanoma model, in which ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. ret-transgenic mice were previously reported to accumulate melanoma-specific effector memory T cells and natural killer (NK) cells in the primary tumors and metastatic lymph nodes. In the present investigation, we monitored effects of artesunate on the CD4 and CD8 T cells as well as Treg and NK cells from ret-transgenic tumor-bearing mice and nontransgenic littermates in vivo. In addition, we investigated cytostatic and cytotoxic activity of artesunate on ret-tumor cells established from the mouse primary tumor. Artesunate inhibited growth of ret-tumor cells and induces their apoptosis in a concentration-dependent manner (0.1-200 micromol/l). Furthermore, we did not find considerable effects of artesunate on the immune function as measured by major cell populations of the immune system; that is, CD4 and CD8 T cells as well as Treg and NK cells both from ret-transgenic mice and nontransgenic C57BL/6 littermates treated for 2 weeks with a daily dose of 1 mg artesunate. These results indicate that the cytostatic and apoptotic effects of artesunate are not diminished by concomitant immunosuppression.
Ramacher
Marcel
M
German Cancer Research Center, Skin Cancer Unit (G300), Im Neuenheimer Feld, Heidelberg, Germany.
Umansky
Viktor
V
Efferth
Thomas
T
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D037621:Artemisinins / Q000494:pharmacology* / Q000627:therapeutic use; D000077332:Artesunate; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D007694:Killer Cells, Natural / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
D000970:Antineoplastic Agents; D037621:Artemisinins; D000077332:Artesunate; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse