Transferrin receptor-dependent cytotoxicity of artemisinin-transferrin conjugates on prostate cancer cells and induction of apoptosis.
Artemisinin, a natural product isolated from Artemisia annua, contains an endoperoxide group that can be activated by intracellular iron to generate toxic radical species. Cancer cells over-express transferrin receptors (TfR) for iron uptake while most normal cells express nearly undetectable levels of TfR. We prepared a series of artemisinin-tagged transferrins (ART-Tf) where different numbers of artemisinin units are attached to the N-glycoside chains of transferrin (Tf). The Tf bearing approximately 16 artemisinins retains the functionality of both Tf and artemisinin. Reduction of TfRs by TfR siRNA transfection significantly impaired the ability of ART-Tf, but not dihydroartemisinin, to kill cells. We also demonstrate that the ART-Tf conjugate kills the prostate carcinoma cell line DU 145 by the mitochondrial pathway of apoptosis.
Nakase
Ikuhiko
I
Department of Chemistry, University of Washington, Seattle, WA 98195-1700, USA.
Gallis
Byron
B
Takatani-Nakase
Tomoka
T
Oh
Steve
S
Lacoste
Eric
E
Singh
Narendra P
NP
Goodlett
David R
DR
Tanaka
Seigo
S
Futaki
Shiroh
S
Lai
Henry
H
Sasaki
Tomikazu
T
D017209:Apoptosis / Q000187:drug effects*; D037621:Artemisinins / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering; D011990:Receptors, Transferrin / Q000378:metabolism / Q000502:physiology*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014168:Transferrin / Q000737:chemistry / Q000494:pharmacology*
D037621:Artemisinins; D034741:RNA, Small Interfering; D011990:Receptors, Transferrin; D014168:Transferrin; C031327:artemisinin